United boss Ole Gunnar Solskjaer used the game to give some fringe players and drop some players for a rest.
Ashley Young's presence at right-back saw Aaron Wan-Bissaka out of the line-up, and neither Fred nor Scott McTominay began in midfield.
Instead Juan Mata, Nemanja Matic and Andreas Pereira were in place for United, and Mason Greenwood was given a start after his goal against Everton last Sunday.
Marcus Rashford scored the first goal of the game on 51 minutes as the home side notched three goals in 10 minutes.
Five minutes later Colchester's Ryan Jackson put the ball into his own net, and Anthony Martial then made it three.
After their win, United were drawn against local rivals Manchester City for the semi-finals.
Elsewhere, Duncan Ferguson pulled off another draw, this time 2-2 with Leicester City. However, he saw his team knocked out of the tournament 4-2 on penalties.
Tottenham fight Man Utd for €60m French sensation - Euro Papers