After a goalless opening 45 minutes, the Shrimps stormed to victory thanks to goals from Vadaine Oliver, Andrew Tutte and Kevin Ellison.
For good measure, they also kept their third home clean sheet of the season and climbed to 19th in League Two in the process.
Jim Bentley had made three changes to the Morecambe side beaten at Lincoln City seven days earlier.
A-Jay Leitch-Smith and Liam Mandeville were relegated to the bench with Luke Conlan out altogether after being unable to train on Friday.
That meant Jordan Cranston was moved to left-back with Aaron Wildig coming into midfield, Rhys Oates starting on the right and Oliver joining Jason Oswell in a front two.
The Oliver-Oswell partnership meant the Shrimps’ first-half tactics were more direct than in recent weeks, coming up against a physical Cambridge team hoping to impress new boss Colin Calderwood.
It was Cambridge who had the best first-half chance when Adebayo Azeez dispossessed Sam Lavelle and advanced towards the Morecambe goal.
A poor touch saw the ball run across goal to team-mate Paul Lewis, seven yards out, but his effort was blocked by a scrambling defence.
George Maris twice chanced his arm from long distance, as did skipper Gary Deegan, without seriously troubling Mark Halstead.
At the other end, Oswell headed off target and Oliver fired over in stretching to meet Cranston’s cross.
It was Cranston who came closest when, after Oswell was brought down just outside the box, his free-kick was saved by David Forde.
However, after an even first half, it was the Shrimps who dominated the second period as they changed approach in moving to a more passing style.
Steve Old had a header blocked, Cranston’s corner was tipped behind, while Ellison shot narrowly over and then saw another effort kept out by Forde’s legs.
The deadlock was broken on 64 minutes when Oswell flicked Cranston’s pass over the top of the defence and Oliver beat Forde to the ball to finish calmly.
Forde kept the visitors in the game with further saves from Oswell and Ellison but was powerless to prevent the Shrimps from wrapping up victory.
Moments after coming off the bench, Tutte played the ball up to Oliver, raced onto the return pass and beat Forde with a fierce shot from a tight angle.
Then, in the second of five added minutes, Morecambe worked the ball beautifully for the outstanding Cranston to lay the ball across for Ellison to score his third in five matches.
Morecambe: Halstead, Yarney, Lavelle, Old, Cranston, Oates (Mandeville 58), Kenyon, Wildig (Tutte 83), Ellison, Oliver, Oswell (Leitch-Smith 83). Subs not used: Szczepaniak, Mills, Mendes Gomes, Hedley.
Cambridge United: Forde, Halliday, Darling, Taylor, Carroll, Lewis (Osadebe 67), Deegan, O’Neil, Dunk (Lambe 79), Maris, Azeez (Amoo 67). Not used: Mitov, Tafte, Davies, Brown.
Referee: Eddie Ilderton.