The Swede marked his return to the first-team with a penalty, while the Bari native scored a fine goal of his own, as the hosts picked up three points
A penalty from Zlatan Ibrahimovic and a delicate Antonio Cassano chip were enough for the Serie A holders to prosper on the night.
The match began with Plzen setting their stall out from the first minute. The visitors had started their Champions League campaign in reasonable fashion, drawing 1-1 against BATE Borisov on the first matchday and they looked to capitalise on the break at every opportunity.
Massimiliano Allegri's side seemed buoyant with the return of Ibrahimovic in their ranks, but his comeback possibly overshadowed the impact of his team-mates initially, as the talismanic Swede was central to virtually every attack at the Czech outfit's goal.
However, it was Plzen who had the game's first chance and it needed a save from the top drawer from Christian Abbiati to deny Vaclav Pilar's bullet header inside the third minute. Unsurprisingly, Milan began to dominate the possession, as the contrasting playing styles made for a fascinating state of affairs.
The hosts continued to search for a breakthrough and they came close through the feet of Ibrahimovic, who profited from Cassano missing his header at the far post, but his powerful strike could only warm the hands of Marek Cech, who pulled off a marvellous stop from close range.
Plzen then created an opportunity of their own, as Pavel Horvath blazed over a free shot at goal inside the Milan box near the end of the first half, with Abbiati seemingly in no-man's land.
However, the second half was a stark contrast to the first 45, as Milan stepped up several notches and broke the deadlock on 53 minutes. Marian Cisovsky's handball led to a penalty and Ibrahimovic netted the spot-kick with ease, sending Cech the wrong way.
The Italian champions doubled their lead through a counterattack 13 minutes later, as Ibrahimovic once again led the way with an inch-perfect through ball to Cassano, who finished with aplomb, lifting the ball over an onrushing Cech.
A late raid of sorts at the Milan goal ensued by Pavel Urba's men, but the wall of Alessandro Nesta and Thiago Silva stood tall, as the Italians earned the first three points of their Champions League Group H campaign.
Allegri's side top the section, just ahead of rivals Barcelona, as Group H continues to form so far.