The Hatters were unable to do so as Millwall took their chances and ended up running out 3-0 winners to book their place in the last eight.
Read how it all unfolded in our minute-by-minute updates below.
12.16pmAfternoon everybody! Surely the Hatters can't do it again can they? We said that about Bradford about seven times in this year's League Cup though.
12.17pmAnyway, there's no time to waste as the teams have been announced...
12.17pmLUTON XI: Tyler, Taylor, Henry, Kovacs, Howells, Lawless, Smith, Mendy, O'Donnell, Gray, Rendell
12.18pmMILLWALL XI: Forde, Dunne, Trotter, Hulse, Lowry, Henry, Feeney, Beevers, Keogh, Abdou, Osborne
12.20pmAs mentioned above, Luton have had a stunning run in this year's competition. By beating Norwich they became the first non-league side to knock out a top flight team since 1989.
12.21pmKenilworth Road is expected to be packed out as Luton fans enjoy a rare day in the spotlight. Around 1,500 Millwall fans are expected to make the short trip North.
12.24pmMillwall manager Kenny Jackett tells ESPN that today's match is both a potential banana skin and a fantastic opportunity to progress to the quarter-finals. "We have to play the game rather than the occasion," he says.
12.25pmJackett adds that Danny Shittu is missing from the side because of a slight knock to his ankle. He expects the big centre-half to be fit for their next match.
12.25pmShittu scored the first goal in the last round when Millwall piled more misery on Aston Villa.
12.28pmPress Assocation journalist Simon Peach tells us on Twitter that there is "huge police presence" in Luton today.
12.29pmThese two clubs have met five times in the competition and Millwall have won four of those matches. They're heavy favourites today but anything could happen, right?
12.30pmPREDICTION TIME! With 15 minutes until kickoff, it's time for doomed prediction. Unfortunately I'm not feeling overly bold today and I'm going with a 2-1 away win.
12.33pmLuton's big-name chairman Nick Owen has been speaking to ESPN and he's delighted to have such a big day at Kenilworth Road. He reveals that he thinks their cup run has earned the club around £500,000.
12.36pmLuton manager Paul Buckle tells ESPN that his players have been shown a motivational DVD and that he's hoping they "put on a great show".
12.38pmMillwall will prove extremely tough opposition as their recent record in the FA Cup is very good. The Lions made it to the fifth round last year as well and they'll be hoping to go one better this time around and maybe go on to replicate their run to the final nine years ago when they lost to Manchester United at the Millenium Stadium.
12.41pmREFEREE WATCH: Today's man in charge is Lee Probert. He leads the two sides out of the tunnel to a bouncing Kenilworth Road.
12.44pmLuton are in orange tops, navy shorts and white socks while Millwall don navy tops, white shorts and navy socks. Kickoff imminent...
3 minFirst shot of the game comes from Luton's top scorer Gray. He is found well on the edge of the box and shoots on the turn but it's straight at Forde.
3 minCHANCE! Millwall go down the other end and Kovac allows Hulse to get the run on him and suddenly he's through on goal but drags his left-foot shot wide of the far post.
6 minGray was touted as the one to look out for in a Luton shirt and he's just created more problems for Millwall. Shittu allowed him to turn far too easily and he tried to beat Forde at his near post but didn't get enough power on his shot.
7 minLight-hearted moment as Gray tries to sneak the ball from Forde by standing directly behind the Millwall keeper. However, they're at the end Millwall end and the visiting fans warn their keeper in a pantomime-style 'He's behind you' moment!
8 minMillwall striker Keogh isn't happy with Luton defender Smith and looks to be trying to goad the Hatters' number 24 into a fight but he isn't biting.
12 minGOAL! Luton 0-1 Millwall (Henry)
12 minLuton can't make mistakes like this if they're to have any chance of causing an upset. A long ball is headed backwards and Kovacs miscontrols with his knee to allow Henry to run in on goal. Kovacs tries to get back and slides in on the Millwall man who could have gone down but stayed on his feet to round Tyler and slide into an empty net.
15 minThat goal was slightly against the run of play and Luton are already back dominating the ball as Mendy sees his shot deflected out for a corner. Lawless takes it but it's too close to Forde who catches easily.
17 minO'Donnell has looked extremely lively down the left side for Luton but hasn't quite got his delivery right yet.
17 minSAVE! Will Luton come any closer to a goal today? Henry floats up a free kick to the back post and it's headed back across goal for Mendy who strikes the bouncing ball very well but it's straight at Forde who parries it away. It almost falls back for a Luton player but Dunne clears away well.
18 minLuton, apart from that one glaring error for the goal, have been outstanding so far and again get in behind the Millwall backline but Taylor's cross is plucked out of the air by Forde.
24 minThe pitch at Kenilworth Road really is of a poor standard as it cuts up more and more with every passing minute. Little to report in the last five minutes but Luton remain the stronger of the two sides.
27 minWonderful wing play from Henry to escape two lunging Luton players on the left. He just manages to keep the ball in and dig out a cross for Hulse but it's behind the big man and he can only hook it over the top from 12 yards.
29 minGray again proves that he's the hosts' main threat but can't work space for a shot before the chance goes as Howells's cross is headed clear by Lowry. They're only a goal behind Luton and playing like a side who know they're in this one.
32 minMore excellent build-up by the Hatters as Gray threads the ball through for O'Donnell making a run down the inside left channel. He pulls it back but Beevers defends well in the middle.
36 minGOAL! Luton 0-2 Millwall (Hulse)
36 minIt's a first Millwall goal for Hulse and I don't think he'll score another one like it in his career! Henry does well down the right to fashion a cross and Hulse meets it at the back post but can only head it up and slightly behind him. He gets to the ball first and loops it acrobatically back across goal and it simply drops in the far corner. I doubt he was going for goal there, just trying to get it back in the middle but it's gone in.
39 minThat's really, really harsh on Luton as they've had more of the play but conceded both of Millwall's shots on target.
40 minI hope this isn't true but PA journalist Simon Peach says that something may have been thrown towards Hulse when he was celebrating that second goal.
42 minWhoever's running Luton's official Twitter feed doesn't mind having a bit of fun! "Atmosphere gone up a ge.....a....r. Sorry...just waiting for the Millwall keeper to take his goalkick #snooze"
45+1 minThree minutes added on at the end of the first half.
45+2 minCHANCE! Almost exactly what was needed at the break for Luton as Howells's corner reaches Kovacs at the back post but Osborne edges him out enough so that he can only head it away from goal.
45+3 minHALF-TIME: Luton 0-2 Millwall
1.38pmIt looks like the Hatters' dream run in the cup is coming to an end then. They've been quite superb in this half but just haven't taken any of their chances. Millwall have had three down the other end and two have ended up in the back of the net.
1.40pmI mentioned earlier how there was an high number of police officers at Kenilworth Road today and here's why. PA journo Simon Peach took a video of fans piling in to the 'Nick Owen' lounge for a half-time beer. Click here to see it.
1.43pmThe stats highly favour Millwall. @OptaJoe tells us on Twitter: "33 - Millwall haven't lost any of their last 33 FA Cup ties when they've scored 2+ goals, a run stretching back to Dec 1983. Safe."
1.46pmMy pre-game prediction of 2-1 Millwall is still on and I'd be amazed if Luton don't at least get one goal back in the second 45.
1.50pmThe two teams are back and ready to begin the second half. Neither manager made any changes.
46 minKICKOFF: Millwall get the second 45 underway.
46 minMendy looks for Gray over the top and he would have been in but for Osborne's header on the stretch.
51 minMillwall have actually started this half the stronger despite their two-goal lead. Luton need something and they need it soon.
54 minYELLOW! First booking of the match is for Luton's Rendell for a mistimed tackle.
54 minCHANCE! Gray is played in on goal and his pace means he gets there just before Millwall keeper Forde. He can't beat the veteran stopper though who spread himself well.
55 minGood spell from Luton now as Kovacs heads Howells's corner just over the bar.
58 min"WHEY!" jeer the Luton faithful as Keogh drags his shot horribly wide of Tyler's goal. The Lions are still looking pretty for a place in the last eight, mind.
59 minLuton's final ball has been the worst part of their game today and another good chance comes to nothing as Lawless simply floats the ball up for Forde to catch.
63 minWonderful pass from Smith inside to Gray but for once the striker's touch lets him down and Forde is there to smother the ball.
64 minLUTON SUB: Stuart Fleetwood takes the place of O'Donnell. The winger got into good positions a lot but struggled to get his head up and was often dispossessed or didn't put in a good enough cross.
66 minCHANCE! N'Guessan's shot is blocked but the loose ball plops straight to Keogh. He can't keep his shot down under pressure from Hatters keeper Tyler.
68 minMillwall are looking very dangerous on the counter now as the fresh-legged N'Guessan sprints clear of the whole Luton midfield before picking out Henry on the left. He cuts back in onto his left and clips a cross to the back post that can't quite be scrambled home.
69 minLUTON SUB: The composed Mendy's afternoon is over as striker Jon Shaw takes his place.
70 minMILLWALL SUB: Another change for the visitors as John Marquis comes on for Rob Hulse, who scored his first goal for the Lions to put them two ahead.
74 minGood patient play from Luton doesn't quite work out as Rendell makes his run slightly early and is caught offside. There's been little from the home side to get the crowd going this half but they enjoyed that.
75 minCHANCES! Millwall almost put the game to bed as Keogh has a pair of great chances. First he saw his instinctive shot beaten away by Tyler before missing the simplest of free headers at the back post from a clever Henry cross.
80 minHowells whips in a corner and it's headed out to Lawless who goes for the spectacular but pulls his volley wide. Millwall need a goal fast if they're to have any hope of snatching a draw.
83 minATTENDANCE: It's Luton's highest turnout of the season with 9,768 inside Kenilworth Road, 1,530 of whom are away fans.
86 minGOAL! Luton 0-3 Millwall (N'Guessan)
86 minNice, one-touch football on the edge of the box results in Marquis looking for the far corner with a placed effort. Tyler reads it but can only palm it out to N'Guessan who bundles it home from a few yards.
89 minMILLWALL SUB: I was about to announce Henry as my man of the match as he comes off for Adam Smith.
90+1 minFour minutes added on at the end. This one's been over quite a while now, unfortunately.
90+2 minBOOKING! One of the most obvious cautions you'll see as Fleetwood nutmegs Beevers and the Millwall centre-back simply tugs him down.
90+3 minSAVE! A Luton corner eventually reaches Shaw all alone at the back post and he drills it low at Forde who does well to kick it away for another corner.
90+4 minLuton end the match gallantly as Gray fires a volley straight at Forde from a tight angle.
90+5 minFULL-TIME: Luton 0-3 Millwall
2.42pmIt didn't turn out to be the cup tie we all hoped for as efficient Millwall took their chances against dogged Luton.
2.44pmIt's a first FA Cup quarter-final for nine years for Millwall while non-league Luton's dream run in the cup comes to an end.
2.46pmThanks for joining Sports Mole this afternoon. Our match report is already up on the site and you can read it here or, alternatively, head over to join Liam Apicella for live coverage of the tie between Arsenal and Blackburn by clicking here. Good afternoon.