Ibrahimovic, returning after a two week absence through injury, broke the deadlock in the 53rd minute after a penalty awarded for handball which the Czech champions protested was accidental.
Thirteen minutes later, the Swede poked the ball through for Cassano to chip the ball over goalkeeper Marek Cech.
The win left the Serie A champions with four points from two games in Group H and Plzen, making their debut in the tournament, with one.
Hosts Milan were given an early fright when Marek Bakos headed wide, but then took control.
Cech twice denied Cassano in the first 10 minutes, the first with his legs from close range when the striker looked set to score while he made an equally impressive save to foil Ibrahimovic.
However, the Czech champions were anything but outclassed and their 36-year-old playmaker Pavel Horvath shot wide with only Christian Abbiati to beat following an incisive move through the centre of the Milan defence.
Urby Emanuelson fired over for Milan early in the second half before Ibrahimovic broke through.
Plzen refused to lie down and Horvath wasted a chance to equalise, shooting weakly at Abbiati from the edge of the penalty area.