Edin Dzeko, Yaya Toure and the outstanding Sergio Aguero all struck in the space of 10 minutes early in the second half as City overpowered their first Group D opponents at the Doosan Arena.
City were not at their most fluid before the break but still went close as Aguero struck the post and Dzeko and Jesus Navas brought good saves out of Matus Kozacik.
The win means City, bidding to reach the knockout stages for the first time after two successive failures, have already equalled their points tally from last season's dismal campaign.
It also lifts confidence after a mixed start in the Barclays Premier League and ahead of next Sunday's derby against rivals Manchester United at the Etihad Stadium.
Manager Manuel Pellegrini said: "I think it is very important to start the Champions League winning away.
"It was not an easy match, against a very good team. Winning 3-0, of course we are very happy.
"It will give confidence for all the players.
"We have the derby next Sunday and always winning away in the Champions League, scoring three goals, having at least three or four more chances to score and a clean sheet - I think it will give all the players a lot of confidence for the next games."
Dzeko, who was denied at point-blank range by Kozacik in the first half, opened the scoring after being set up by Aguero in the 48th minute.
Toure doubled the lead with a superb strike from distance and Aguero added the third after a smart turn and shot from the edge of the area.
Dzeko said: "Our quality was better in the second half, but Plzen also played some good stuff in the first half.
"We had chances and didn't score, but then the goals came.
"The manager told us to keep playing our football and be organised, to concentrate and be aggressive, and that the goals would come. They came."
City, unconvincing in their most recent games, also looked better for the return of captain Vincent Kompany at the back after a three-game absence with a groin injury.
Right-back Pablo Zabaleta said: "It was a good performance by the team.
"We played well, especially in the second half when we came up with some good football.
"Having Vincent back was good. He is the captain and leader of the team, and it's always good to have him in the team."
Pellegrini is also hopeful playmaker David Silva will be fit to return for the derby after two games out with a thigh injury.
The Spaniard will be assessed later this week, as will defender Gael Clichy, who has been out with hamstring trouble.
Pellegrini said: "Maybe they could arrive for the derby. We will see during the week. I think Clichy is more difficult but we will still try."
- Sports & Recreation
- Sergio Aguero
- Edin Dzeko
- Manuel Pellegrini
- Barclays Premier League