The Portuguese outfit qualified from Group D as runners-up to set up a last-32 tie with Arsenal, who swept aside the competition in Group B to progress in first place.
With any prospects of an audacious bid for the title now seemingly dead in the water, Benfica may very well decide to prioritise the Europa League due to their underwhelming league fortunes in recent weeks.
Jorge Jesus's men warmed up for this game with a disappointing 1-1 draw against Moreirense, where Haris Seferovic took his tally to 12 for the season in all competitions before Yan restored parity for the hosts, and Benfica have now won just one of their last six Primeira Liga outings, drawing four of them.
The fourth-placed Aguias now find themselves 13 points adrift of runaway leaders Sporting Lisbon after 19 games, despite having lost just three league matches all season, but at the very least, they head into the first leg on a four-game unbeaten streak following success in the Taca de Portugal earlier this month.
Jesus witnessed his side navigate their Europa League group-stage campaign unbeaten, but as has been the case with their top-flight fortunes, failure to convert draws into wins saw them qualify in second behind Rangers, although the 18 goals that they notched up was the third-highest across all groups behind Bayer Leverkusen and their midweek opponents Arsenal.
With the away goals rule still in play despite the fixture being moved due to coronavirus travel restrictions, Benfica's rearguard must quickly find their resolve if they are to keep Arsenal at bay, but that will be easier said than done against a rejuvenated Pierre-Emerick Aubameyang.
Arsenal's normally prolific captain has been dealing with issues on and off the pitch during the current campaign, but he marked his return to the starting lineup in perfect fashion with his first Premier League hat-trick against Leeds United in a 4-2 triumph on Sunday.
Hector Bellerin also answered his critics with a goal on the day, and even though Marcelo Bielsa's team threatened a comeback with two second-half goals, Mikel Arteta's men held on to give their fans something to cheer about after back-to-back defeats to Wolverhampton Wanderers and Aston Villa.
However, the Arsenal manager himself has conceded that his side cannot be considered realistic challengers for a top-four finish, so once again, the Europa League arguably represents the Gunners' best opportunity to return to the biggest stage of them all, and Arteta will be desperate to avoid a repeat of last season's humiliating last-32 exit to Olympiacos.
As mentioned, Arsenal simply strolled their way through their group with Dundalk, Molde and Rapid Vienna, with their goal difference of +15 the joint-highest out of all 48 teams alongside Hoffenheim, and no other club in the group stage advanced with six wins out of six - potentially a good omen for Arteta's side ahead of their trip to Rome.
The Emirates faithful would love nothing more than for their side to go all the way and bring a European trophy back to the English capital, and they have only ever met Benfica twice before in the 1991-92 European Cup, where the Portuguese side advanced 4-2 on aggregate in the second round.
Benfica Europa League form: WWDDWD
Benfica form (all competitions): WLDWWD
Arsenal Europa League form: WWWWWW
Arsenal form (all competitions): LWDLLW
Jardel is another long-term absentee for the Portuguese side, who should welcome Odysseas Vlachodimos back in between the sticks, while Pizzi - tied with Lille's Yusuf Yazici at the top of the Europa League scoring charts with six - will also hope to return to the first XI.
Arsenal have confirmed that they will speak to Aubameyang over an alleged breach of coronavirus protocols, but at this stage there is nothing to suggest that he will not be involved on Thursday.
The Gunners captain did take a kick to the ankle in the dying embers against Leeds but should be fine for this one, but there is less optimism over the fitness of Thomas Partey and Kieran Tierney, both of whom are likely to miss out.
Nicolas Pepe struck three times and provided three assists in the group stage, and given the fact that Benfica may have to do without both recognised right-backs, the Ivory Coast international will be hopeful of starting on the left-hand side.
Benfica possible starting lineup:
Vlachodimos; Goncalves, Otamendi, Vertonghen, Grimaldo; Silva, Taarabt, Weigl, Pizzi; Nunez, Seferovic
Arsenal possible starting lineup:
Leno; Bellerin, Luiz, Gabriel, Cedric; Xhaka, Ceballos; Saka, Smith Rowe, Pepe; Aubameyang
We say: Benfica 1-2 Arsenal
Arsenal are incredibly difficult to predict at the moment, but so long as they manage to keep 11 men on the pitch and get their young guns firing on all cylinders, they have a strong chance of advancing to the next round. Benfica have also flattered to deceive in the league but are capable of making it a challenging evening for the Gunners, although we still expect Arsenal to take a narrow advantage into next week's second leg in Greece.