Alvaro Negredo and Edin Dzeko struck in the last 12 minutes from time as the Premier League outfit made hard work of seeing off the Czech champions on Wednesday and they can still win the group with a strong victory at Bayern Munich next month.
In-form striker Sergio Aguero put Manuel Pellegrini's side in front from the penalty spot with his 15th goal in his last 12 games after Frantisek Rajtoral was harshly adjudged to have handled in the area. However, the Czechs were level at the break courtesy of an impressive strike from Tomas Horava.
Samir Nasri put City back in front, but Plzen levelled for a second time in a frantic encounter when Stanislav Teci fired home.
Negredo put City in front for a third time when he finished from close range and Dzeko sealed the points at the death as City took their tally to 22 goals in their last four home games.
Joe Hart made his first City start for a month after being dropped for the last five games as Manuel Pellegrini made seven changes to the side which hammered Tottenham 6-0 on Sunday.
Roman Hubnik came in at left-back for Plzen to replace David Limbersky, out with a stomach problem.
Nasri looked in the mood early on, rattling the crossbar with a vicious right-footed strike after 13 minutes.
Plzen were not content to sit and soak up pressure though, and they could have taken a surprise lead after 26 minutes when Rajtoral raced into the box and flashed the ball across the face of goal.
Rajtoral’s disappointment at spurning that opportunity was compounded 12 minutes before the break, when he was harshly adjudged to have handled in the area and Aguero sent Matus Kozacik the wrong way from the spot.
Plzen gave as good they got in the first half and they were deservedly level two minutes before the interval, when Horava rounded off a slick move with a right-footed strike into the far corner that gave Hart no chance.
Jesus Navas replaced Aguero at the break and they were almost back in front when Fernandinho's header was tipped over by Kozacik.
But the goalkeeper was beaten after 65 minutes, when Yaya Toure made an immediate impact after coming on when he laid the ball off for Navas, whose cross was volleyed home left-footed by an unmarked Nasri.
Hart produced an outstanding reflex save to tip over Daniel Kolar's long-range drive a minute later, but Tecl capitalised on some hesitant City defending to equalise with a measured right-foot finish from inside the area with 20 minutes to go.
There was still time for a final twist and Negredo provided it as he converted a Navas cross and Dzeko had the final say with he headed home an inviting James Milner cross at the back post to seal the points.
STATS ZONE Man City 4-2 Viktoria Plzen analysis
