The Premier League champions took the lead after only 12 minutes when Raheem Sterling broke the deadlock, but it took until the end of the first half for the floodgates to really open.
A Phil Foden finish and Semi Ajayi own goal in quick succession right on the stroke of half time allowed the hosts to run riot after the break, with Gabriel Jesus, Riyad Mahrez, Nicolas Otamendi and Leroy Sane all getting in on the act in the second half.
The seven different goalscorers condemned Rotherham to their heaviest ever FA Cup defeat as Man City cruised into the next round and never looked in danger of succumbing to an upset.
The latter pair linked up within two minutes to almost break the deadlock when De Bruyne's cross into the box was met by Jesus, who clipped the top of the crossbar with his header when he should have done better from close range.
That was only the first of a flurry of chances for the home side in the opening exchanges as they sliced the Rotherham defence open almost every time they came forward, and Sterling - one of only three players to keep their place in the team - sent the ball flashing wide moments later after Ajayi's last-ditch challenge had rebounded off his shin.
Jesus squandered a second gilt-edged chance in the opening 10 minutes when he missed the ball from Mahrez's low cross into the six-yard box, and Mahrez himself then drew a first save from Marek Rodak with a cross/shot from a tight angle.
An early goal seemed inevitable and it arrived in the 12th minute when De Bruyne slid a pass into the box for Sterling, who danced past Ajayi before curling his finish into the bottom corner.
At that stage it looked as though it might be damage limitation mode for Rotherham already, but the visitors responded well and Ajayi saw one shot deflect wide before Clark Robertson nodded over from the resulting corner.
Ederson then got away with a lax piece of play when he was caught in possession on his own byline, but he was fortunate that the ball fell to John Stones, who was able to clear from inside the six-yard box.
City immediately responded with a chance of their own, although Jesus's misfiring first half continued when he failed to turn De Bruyne's low cross in from close range.
Rotherham will have been content with their first-half performance after falling behind, though, and it looked as though they might make it to the interval with only a one-goal deficit until Man City doubled their lead one minute before the break.
Ilkay Gundogan clipped a pinpoint pass into the area for Foden, who took the ball down but then saw it bounce against his knee and squirm past the keeper for a muddled finish.
An almost identical move unlocked the Rotherham defence again moments later with Mahrez on the end of it this time, but his close-range header was straight at Rodak.
However, City did make it two goals in quick succession at the end of the first half and again there was a hint of fortune about it as Ajayi could only turn Kyle Walker's low cross into his own net when trying to deny Sterling a simple finish.
It could have been even worse for the Championship strugglers when City came pouring forward again before half time, but this time Sterling sliced his finish after the visitors had given the ball away inside their own half.
The late salvo made a previously competitive Rotherham grateful to hear the half-time whistle, but Man City quickly picked up where they left off upon the restart and Rodak turned an early De Bruyne effort wide in the second half.
A fourth goal arrived just eight minutes after the break when Sterling turned provider, showing electric pace down the left wing before playing a low pass into the box which left Jesus with a simple finish into an empty net.
It was one-way traffic from that point on as Rotherham simply tried to avoid a heavier drubbing, and Mahrez fired one effort over before Jesus drew another save from Rodak after good footwork in the area.
It took a smart reaction save from the keeper to deny a second own goal when he clawed Will Vaulks's sliced clearance off the line, but City's fifth followed soon after as Mahrez swept home his finish after a slick one-two with Gundogan.
The floodgates had well and truly opened by that stage, and Walker stung the palms of Rodak with a powerful long-range strike before City made it six through Otamendi, who rose highest to plant his header into the corner.
That goal left Rotherham staring down the barrel of their heaviest ever defeat in the competition - which before today was 6-0 - and Sane confirmed that unwanted record five minutes from time when his right-footed strike from outside the area took a big deflection on its way past the keeper.
The Millers were once again left to rue a bad piece of luck, although they could have no complaints at being soundly beaten as the significant gulf in class told between the Premier League champions and second-tier relegation candidates.
There was one late chance for Rotherham to take some kind of consolation when Anthony Forde picked out Michael Smith in the area, but the striker fired straight at Ederson with just two minutes remaining and the referee soon put the visitors out of their misery.
The result sees City end an 11-game wait for a clean sheet ahead of their EFL Cup semi-final first leg against Burton Albion on Wednesday, while Rotherham must look to shake this beating off ahead of next weekend's Championship battle with fellow strugglers Ipswich Town.
MAN CITY (4-3-3): Ederson; Walker, Stones (Danilo 75'), Otamendi, Zinchenko; De Bruyne (Sandler 67'), Gundogan, Foden; Mahrez, Jesus, Sterling (Sane 57')
ROTHERHAM (4-5-1): Rodak; Vyner (Wood 89'), Ajayi, Robertson, Mattock; Forde, Vaulks, Wiles, Williams (Palmer 90'), Taylor (Wood 90'); Smith