As the scoreline suggests, United were convincing in returning to winning ways on Tuesday evening.
Two goals from Jose Baxter and first goals for the Club from Matt Done and Jay McEveley secured the emphatic success.
The victory also marked United's first double of the season and the first four-goal haul of the campaign.
New boy Done was handed his Blades debut as chief Clough's teamsheet showed three changes. The January transfer window deadline day signing started, as did skipper Doyle and Campbell-Ryce. Davies, Reed and Adams dropped to the bench. Former Blade Porter started for Colchester.
However, at kick-off it became apparent that a fourth change had been made with Turner starting in goal after first-choice Howard suffered a recurrence of a back problem in the pre-match warm-up. The replacement stopper was called upon within 45 seconds, kicking away a Szmodics front post clip after Massey's pull-back. The early atmosphere inside S2 was subdued but a goal with the first Blades attack warmed up the crowd.
A Gordon foul on Brayford resulted in Campbell-Ryce swinging in a free-kick and BAXTER forced the ball in at the back post at the second attempt, despite the efforts of Fox and goalkeeper Walker.
Colchester attempted to hit back and forced a number of corners as they searched for a leveller. Fox volleyed wide from distance and on 24 minutes the visitors went very close through a familiar face. A Campbell-Ryce slip allowed Colchester to break, a Briggs pass put Porter in space and his shot was on target before Turner dropped to his right to push around the post.
Coincidentally, it was a break at the other end that extended United's lead on 37 minutes. From a Colchester corner, Murphy laid off to Harris, who delivered a crossfield ball for DONE to run onto and cut inside before curling, left-footed, into the bottom corner of Walker's net.
The remainder of the first half saw nothing additional in terms of attacking intent but United looked comfortable in protecting Turner's goal and the two goal cushion.
Early in the second half Done thought he had recorded his second until referee Sarginson intervened - the official adjudging the new striker controlled with his arm before slotting home Brayford's cross.
United's third, however, was not far away, although it came from an unusual source. There seemed little danger for the visitors when Coutts laid off to McEVELEY, who was afforded space to travel forward before unleashing a 30-yard shot, which easily beat Walker, defending the Kop goal.
Just after the hour, Holt made his home debut, replacing Campbell-Ryce, quickly followed by McNulty taking over from the tiring Done, who received an ovation from the Blades fans.
Colchester were given a glimmer with 20 minutes to go when a pass from Semble-Ferris enabled SZMODICS to curl beyond Turner's right hand.
The visiting side's revival, however, lasted little more than ten minutes as United added a fourth. A pass from Coutts was cut out but he won back possession and was then impeded by Briggs just inside the box, referee and his assistant agreed that a penalty was the right decision. BAXTER took responsibility for the spot-kick and slammed home in front of the Kop.
In the final ten minutes, Adams took over from Murphy and United continued at a decent tempo, despite having the game in the bag. McNulty wasted a chance from a Coutts cross before the visitors should have reduced the arrears in injury-time. Turner dropped a cross but the central defensive duo of Basham and McEveley made goal-line blocks from McEvoy to protect the three-goal margin
Blades: Turner, Harris, Brayford, Basham, Doyle, Murphy (Adams 82), Baxter, Done (McNulty 67), Coutts, McEveley, Campbell-Ryce (Holt 61).
Unused: Willis, Davies, Reed, Kennedy.
Colchester: Walker, Wynter, Gordon (Sembie-Ferris 52), Briggs, Eastman, Clohessy, Massey (McEvoy 88), Szmodics, Lapslie, Fox, Porter.
Unused: Watt, Marriott, Lewington, Vincent-Young, Bonne.