The U's found themselves three goals down with thirty minutes to play when strikes from Nouble and Eastman gave Mullins' side hope of a revival.
Two goals in the first half from McAleny and McCalmont put the Latics 2-0 ahead at half time before Carl Piergianni added a third to seemingly put the game beyond doubt ten minutes into the second half.
But well taken strikes from Nouble and Eastman gave the U's hope that they might steal a point from an impossible position, before Davis Keillor-Dunn sealed the game with an injury time brace to make it 5-2 and ensure that Oldham were the side to take all three points.
Hayden Mullins made one change to the starting eleven that lined up against Barrow on Easter Monday, with Tom Eastman coming in for Jevani Brown. The only other changes were to the bench, with Cowan-Hall and Sowunmi named as substitutes in place of Josh Doherty and Junior Tchamadeu.
Following on from their 4-1 victory against Crawley at the weekend, it was Oldham that started the game the brighter. Colchester United were just taking a little more time to get into the game, with dangerous runs from Fage cut out on the right flank by Ryan Clampin.
Dylan Bahamboula was a dangerman sitting just behind the main striker, and he had a couple of sighters in te opening ten minutes without testing Gerken. Both shots were dragged wide, but it was a sign of what the Oldham man could do.
But Colchester United were so close to taking the lead and profiting from a mistake at the back from the Oldham defence. A poor back pass to Walker bobbled as the 'keeper kicked it, striking Brendan Sarpong-Wiredu, but unluckily not going in the net off the midfielder's leg.
The home side were the ones to get their noses in front first with ten minutes to go until half time. Tom Eastman's foul on Keillor-Dunn in the penalty area allowed McAleny to convert from the spot, despite Gerken getting fingertips to the ball.
And five minutes later, the hosts doubled their advantage. This time it was a free kick that had the beating of Gerken, from McCalmont's right foot. His curling strike from the right hand side of the D clipped the post on its way in, leaving Colchester United with it all to do in the second half.
The U's would have their work cut out to get anything from the game as the teams appeared for the second half, but ten minutes in, Carl Piergianni effectively put the game to bed. The centre back attacked the ball from a corner and smashed it home at the second attempt.
Frank Nouble was unfortunate not to reduce the deficit in the sixtieth minute. Following in from Harry Pell's low drive, the ball struck the post before Nouble lifted his effort over on the follow up.
But Nouble got his name on the score sheet two minutes later. Good work from Clampin released the front man, and he finished with aplomb, driving the ball through Walker's legs to make it 3-1.
Hayden Mullins' side were pushing forward in numbers and were open to counter attacks, but reduced the deficit yet again. This time is was Tom Eastman with a strike from range that evaded Walker to make it 3-2 with eight minutes to go.
The U's continued to push men forward to press for an equaliser. They thought they had it through Michael Folivi as he cleverly looped the ball into the net, but his goal was ruled out for an apparent push. Ryan Clampin raced through, riding challenges from both sides as he pulled the trigger, but Walker was able to save as time was running out.
And Oldham were able to hit the U's on the counter attack. David Keillor-Dunn added the fourth as the game entered injury time, and a fifth for the hosts with less than a minute to play.
The result leaves the U's on forty-one points, now having played forty-one games. Next up for Colchester United, Walsall visit the JobServe Community Stadium on the 17th April.
Oldham Athletic starting XI: Walker, Clarke, Borthwick-Jackson, Piergianni, Whelan, Keillor-Dunn, Fage (Hilssner 88'), Jameson (Adams 51'), McAleny (Garrity 70'), Bahamboula (Diarra 88'), McCalmont.
Unused subs: Chapman, Ntambwe, Badan.
Colchester United starting XI: Gerken, Welch-Hayes, Lapslie (Stevenson 79'), Smith, Senior (Brown 57'), Pell, Harriott (Sowunmi 57'), Eastman, Clampin, Sarpong-Wiredu (Chilvers 65'), Nouble (Folivi 65').
Unused subs: George, Cowan-Hall.