City should have been ahead at the break as, barring a couple of minor scares, they dominated at the Doosan Arena before three goals early in the second half saw Manuel Pellegrini's men home in comfortable fashion.
The opener came on 48 minutes when Sergio Aguero's break teed up Edin Dzeko to slot home before Yaya Toure scored a brilliant curling effort just moments later to double their lead.
The third came just before the hour and it was a deserved goal for Aguero as he turned just inside the box before firing into the corner.
After a dismal Champions League campaign last term, which saw them fail to register a win, City will be delighted to begin in such comfortable fashion.
The result was the perfect start in the competition for City's new manager and lifted spirits after a mixed start to the campaign ahead of Sunday's derby against Manchester United.
Pellegrini's previous record in the Champions League, having taken Villarreal to the semi-finals and Malaga to the last eight, was one of City's prime reasons for appointing him in the summer.
A day after his 60th birthday, he got what he hopes will be another prolonged run up and running with a convincing win.
Reigning champions Bayern Munich will doubtless provide a sterner test in their next fixture but City's challenge is already looking better than last season's, when they failed to win a match.
City also looked stronger for the return of captain Vincent Kompany, who had missed the previous three games with a groin injury.
It took City time to make their mark against a Plzen side unbeaten in 14 games this season but once the deadlock was broken the result was never in doubt.
City started brightly with Jesus Navas forcing Matus Kozacik to tip over a powerful shot from the edge of the area.
It was the first of a number of good saves from Kozacik but he was caught out at the resulting corner as Toure headed over.
Dzeko headed another chance over before Jan Koravik missed Plzen's first serious chance.
City had not got into their stride when Aleksandar Kolarov was needlessly booked for handball and Joe Hart had an uneasy moment when he ineffectively punched a free-kick.
Dzeko should have given City the lead after 22 minutes when Kolarov burst down the left and picked him out in the six-yard box but Kozacik saved the Bosnian's header at point-blank range.
Aguero went even closer with a firm low drive which struck the foot of the upright and Kolarov hit the rebound straight at Kozacik.
Navas created another opportunity but his shot took a deflection and the wrong-footed Aguero stumbled and punched the ball.
At the other end Tomas Horava attempted a spectacular volley from a Frantisek Rajtoral cross but shot well wide.
City were far from convincing in the first half but continued to create opportunities and Aguero stabbed against the post again, although the whistle had gone for a foul on Kozacik.
Much to Dzeko's frustration, Aguero shot at Kozacik just before the interval. But the Argentinian was anything but selfish as he set up City's opener three minutes into the second half, muscling his way past Lukas Hejda and racing clear to square for Dzeko who slotted home.
Toure then doubled the advantage with a sublime effort in the 53rd minute, taking a touch outside the area and then curling a shot into the top corner.
Plzen's resolve was broken and they conceded again from long range as Aguero took a pass from Navas and turned just inside the area to drive into the bottom corner.
City were then content to play out the rest of the game but Aguero might have had a second when he broke through after 86 minutes but Kozacik saved.
Negredo came off the bench to create another chance for Aguero in the last minute but he shot over.