A hat-trick by world footballer of the year Lionel Messi and a Cesc Fabregas goal were enough to see off the Champions League debutants.
The clean sheet saw Barcelona goalkeeper Victor Valdes set a new club record of 877 minutes wothout conceding a goal.
Messi converted a penalty, added a second just before halftime and completed his second hat-trick in four days in stoppage time - Fabregas goal came from a header in the 72nd minute.
Barca top Group H with 10 points from four games, two points ahead of AC Milan who also reached the second round despite being held to a 1-1 draw at Belarusian side BATE Borisov earlier on Tuesday.
Messi converted a penalty with a low shot in the 24th minute after being brought down in the box by Plzen sweeper Marian Cisovsky, who was also sent off.
Just before halftime, Adriano played aneat interchange with Messi to set the Argentinian up for a left-footed shot from inside the box that left Plzen keeper Roman Pavlik diving in vain.
Fabregas made it 3-0 with a close-range header after a cross from 20-year-old winger Isaac Cuenca, who had replaced the injured Pedro Rodriguez in the starting line-up.
The Catalans, who beat Plzen 2-0 at the Nou Camp two weeks ago, started with Thiago and Adriano in midfield while coach Pep Guardiola put Andres Iniesta and Xavi on the bench and striker David Villa was rested.
Plzen, playing in Prague as their own stadium fails to meet UEFA requirements, showed a more plucky approach to their one at the Nou Camp.
But winger Milan Petrzela was denied by Barca keeper Victor Valdes after a superb run and midfielder Daniel Kolar sent his shot high over the bar.
Barca then seized control, but Messi was denied three times by Pavlik who also stopped a swerving effort by Fabregas early on.
Fabregas chipped the ball just wide a minute into the second half, Messi's free kick was stopped by a diving Pavlik and Thiago headed onto the bar.
Plzen created just a single scoring chance in the second half as Petrzela blasted a low volley just wide.