Edin Dzeko opened the scoring and Yaya Toure's stunning strike doubled City's lead before Sergio Aguero stunned the Czech champions with a third soon after.
City have failed to progress from the group stage in the last two seasons, but a convincing victory at the Doosan Arena will give them high hopes of an extended run this time around.
City captain Vincent Kompany was passed fit to return from a groin injury sustained during the Premier League opener against Newcastle United and manager Manuel Pellegrini also recalled Fernandinho, Jesus Navas, Dzeko and Aguero for the Group D encounter.
Plzen were unable to call on defensive duo Marian Cisovsky and Radim Reznik, who were both ruled out due to injury.
Plzen goalkeeper Matus Kozacik was called into action after just six minutes to tip Spain winger Navas’ right-foot strike from 20 yards out over the crossbar.
Aleksandar Kolarov was shown a yellow card for handball 16 minutes in and the City defender took a risk when he fouled Milan Petrzela three minutes later, but referee Paolo Tagliavento was happy just to give a free-kick.
Joe Hart fisted away the resulting set-piece from skipper Pavel Horvath, but City responded and Dzeko should have scored when he headed straight at Kozacik after being picked out by Kolarov.
City continued to probe as Aguero rattled the post with a shot from outside the penalty area and Kolarov fired the rebound straight at the keeper but the visitors were unable to break the deadlock before the break.
But City were in front just two minutes into the second half and Aguero was the architect, sliding a pass into the path of striker partner Dzeko, who found the bottom-right corner with a measured left-foot finish.
Dzeko fired over the bar a few minutes later, but City doubled their lead after 52 minutes in spectacular fashion when Toure bent a stunning right-foot strike into the top-right corner of the net from 25 yards out.
City were rampant and they were out of sight when Aguero turned sharply just inside the penalty area and fired home with a clinical left-foot finish.
