An improved second half showing wasn't enough to prevent Town leaving Colchester empty handed and extending their winless run to ten.
A disappointing first half saw Colchester take a two goal lead into the break with Kwesi Appiah and Frank Nouble both getting their names on the score sheet.
Alex Pattison netted early in the second half to give his side hope of getting something from the game, but Colchester were able to withstand the Harrogate pressure and claim three points.
Simon Weaver set his Town side up in a 442, with Jack Muldoon partnering Luke Armstrong in attack and Matty Daly and Danny Grant in the wide positions.
The hosts were ahead after just seven minutes when a long ball wasn't dealt with allowing Appiah to round Pete Jameson and slot into an empty net.
Colchester struck the woodwork in the 23rd minute when Nouble's header connected with the inside of the upright after a cross towards the far post.
Grant's low cross nearly feel for Muldoon with ten to play, but it was soon 2-0 as Nouble made this one count at the back post, this time converting a low cross.
Harrogate's best moment came in first half stoppage time with Daly and Grant both involved in a move that gave Muldoon space to shoot, but Sam Hornby in the Us goal claimed.
Weaver opted for a double change at the break as Captain Josh Falkingham and Vice Captain Warren Burrell replaced Josh Austerfield and Joe Mattock.
Town pulled a goal back 12 minutes into the second half as a loose pass out from the back presented the ball to Grant, who quickly fed Pattison to beat Hornby with a lofted finish.
Weaver's side were putting pressure on the hosts in search of an equaliser, with McArdle glancing a header onto the roof of the net just past the hour mark.
Jameson was called into action in the 77th minute, denying Luke Hannant with a fine reaction save to keep his side within one goal of their Essex opponents.
A last ditch challenge denied Armstrong at the other end before Jameson and Burrell came to Town's rescue. Jameson making a point blank save seconds before Burrell was able to clear the follow up effort from under the cross bar.
Just as the Referee indicated an additional nine minutes Burrell nearly made a telling impact at the other end as his left footed volley was beaten away by Hornby, which was the closest Town would come to forcing a dramatic late equaliser.
Town: Jameson, Mattock (Burrell 45), Grant, Headley, Pattison, Austerfield (Falkingham 45), Muldoon (Coley 84), Ramsay, McArdle, Daly, Armstrong
Subs not used: Oxley, Frost, Dooley, Ferguson
Goals: Pattison 57
Booked: Mattock, Falkingham, Burrell
Colchester: Hornby, Chambers, Dallison, Hannant (Eastman 90+4), Skuse, Appiah (Newby 76), Sears (Akinde 63), Tchamadeu, Kazeem, Miranda, Nouble (Lubala 63)
Subs not used: O'Hara, Clamplin, Longstaff
Goals: Appiah 7, Nouble 38
Booked: Miranda, Chambers
Referee: C Hicks