Downes picked up a fifth booking of the season in Saturday's 1-1 draw with Portsmouth and serves his one-match ban on Tuesday night.
Vice-captain Kyle Storer is back in the mix after a four-game absence, but Robins boss Gary Johnson has plenty of midfield options with Harry Pell, James Rowe, James Dayton and Jack Munns all available.
Former Colchester striker Dan Holman hopes to retain his place in attack against his old club.
Colchester are again likely to be without Luke Prosser, Sammie Szmodics and Chris Porter.
Defender Prosser (knee) and forward duo Szmodics (foot) and Porter (hamstring) are all struggling.
Midfielder Owen Garvan has returned from a pre-season leg injury, but it is likely still too soon for him to be involved in the first team.
Defender Matt Briggs (hip), midfielder Doug Loft (Achilles) and left-back Lewis Kinsella (ankle) are long-term absentees.
Head To Head
Colchester have the better of the head to head between these two sides with a record of four wins, two draws and two defeats. The sides last met in 2009 and it was Colchester that came away with a 3-1 victory.
Cheltenham vs Colchester United Stats
71% of Cheltenham's matches have had under 2.5 goals in total and they have conceded at least one goal in 78% of their home matches. Colchester have failed to win in their last 10 league matches and they have lost their last 4 away matches. 65% of Colchester's goals have been scored in the first half.
