Colchester's position in League Two for the 2018–19 season was confirmed on 21 April 2018, when the U's suffered a 2–1 defeat at Lincoln City, mathematically ruling out potential for promotion through the play-offs.

[6] On 9 May, Academy graduate Drey Wright signed a two-year pre-contract agreement with Scottish Premiership side St Johnstone.

This included Tarryn Allarakhia, Charley Edge, Dominic Kurasik, Eli Phipps, Josh Pollard, Callum Sturgess and JJ Wilson.

[18] On 7 June, Colchester signed former West Bromwich Albion goalkeeper Ethan Ross on a two-year contract, while Wolverhampton Wanderers forward Aaron Collins joined the club in a season-long loan deal.

[20] Meanwhile, three more friendlies were confirmed, with trips to nearby Maldon & Tiptree and newly promoted National League side Braintree Town on 7 and 10 July respectively.

[26] On 5 July, Colchester signed centre back Chris Forino-Joseph on a one-year contract following a trial period with the under-23 side last season.

[34] Colchester's final opponents in the EFL Trophy group stage were drawn on 18 July with Southampton under-21s set to visit the Community Stadium.

Ronnie Vint put the ball into his own net following a cross from Brennan Dickenson after 81-minutes as Colchester battled to a narrow victory over the National League South side.

Substitute Sammie Szmodics registered his first goal of the season 12-minutes after arriving on the pitch in the 79th minute, before debutant Luke Norris scored to level the match at 2–2.

Following a goalless first half, the hosts took an 81st-minute lead through Craig Davies, but Sammie Szmodics goal drew the U's level in the fifth minute of added time to secure a 1–1 draw.

[46] On 21 August, Noah Chesmain signed for Southern League Premier Division Central side Hitchin Town in an initial month-long loan deal.

[49] On 30 August, Tariq Issa signed for Southern League Premier Division Central side Needham Market on loan until January.

After the break, Cheltenham pulled a goal back through Kevin Dawson, but Colchester secured victory in the 88th minute, again from the penalty spot, as Harry Pell converted against his former club.

James Norwood had given the hosts the lead just before half time but Pell's strike on the hour mark earned Colchester a point from the 1–1 draw.

Luke Norris converted from the penalty spot on 81 minutes to give the U's a glimmer of hope of earning some points but they eventually fell to a 2–1 defeat.

[66] On 26 October, young goalkeeper Bailey Vose joined National League South side Dartford in an initial month-long loan deal.

Shortly after top scorer Luke Norris had been stretchered off with an injury against his former club, Sammie Szmodics scored his sixth goal of the season.

After only three minutes, Colchester lost defender Tom Eastman to injury, and then goalkeeper Rene Gilmartin suffered a similar fate after half an hour.

In second-half injury time, Harry Pell scored his fourth goal of the campaign to give the U's hope, but Emmanuel Osadebe struck a third for Cambridge less than a minute later to dump Colchester out of the competition.

[75] Mikael Mandron registered his first goal of the season on 8 December as Colchester beat Sol Campbell's Macclesfield Town 1–0 in his first game in charge of the club.

Colchester were also reduced to ten men in the 89th minute when Frankie Kent was sent off for a second bookable offence, allowing Gambin to score again with the resulting free kick.

[83] On 2 January, Aaron Collins' loan from Wolverhampton Wanderers was terminated by mutual consent after four starts and a total of ten appearances for the U's.

County went further ahead on 32 minutes through Kristian Dennis before an attempted clearance deflected into the net from Mikael Mandron to bring the U's back into the game at 3–2.

[98] Striker Junior Ogedi-Uzokwe was once again loaned out on 6 February, joining League of Ireland Premier Division side Derry City until 30 June.

[101] On 22 February, midfielder Sam Warde joined League of Ireland Premier Division side Sligo Rovers on loan until the end of June.

After a goalless first-half, the visitors took the lead on 57-minutes through Hallam Hope, but Colchester pressed for an equaliser and scored in the 84th-minute through Frankie Kent to draw 1–1 and record an undefeated February.

The result dropped them out of the play-off places, but the match did see the debut of Colchester's youngest-ever first-team player when 16-year-old Todd Miller replaced Courtney Senior in the 87th-minute of the game.

[114] The U's closed the gap to seventh-placed Exeter to just two points on 19 April with a 1–0 home victory over Grimsby, Frank Nouble scoring Colchester's only goal of the game.

[118] Knowing only a win would stand the club any chances of reaching the play-offs, the U's travelled to Champions Lincoln City on 4 May and comfortably won 3–0 with three first-half goals.

However, their attempts were in vain when Newport County equalised at Morecambe in the 87th-minute of their match to pip the U's to seventh place by a single point, spelling a fourth successive season in League Two for Colchester.