With Brett Wilkinson nursing a shoulder injury, Ronan Loughney has been called into the front row alongside Jamie Hagan and Ireland hooker Sean Cronin.
Loughney, a graduate of the Connacht Academy, will be making his 70th appearance for the province this weekend.
Former Harlequin Gavin Duffy is set to start at full-back, despite being troubled by a knee injury, while Darragh Fanning will start on the right wing in place of the benched Brian Tuohy.
Fanning has impressed the Connacht management with his pace and physicality in training and has appeared in seven of Connacht's matches so far this season.
With Loughney promoted and an Achilles injury ruling out Connacht newcomer Rodney Ah You, props Rob Sweeney and Barry Fa'amausili have been added to the replacements bench.
Connacht lie third in the Pool 1 table ahead of the round 4 matches. They have five points, with Harlequins and leaders Bayonne both on ten.
Commening on Friday's return leg against Harlequins and his side's festive run of fixtures, head coach Eric Elwood said: "We need a win. It's as simple as that. We are working extremely hard and we need to get a win to give us the confidence heading into Christmas period.
"Derby matches in the Magners League are very important to everybody, and we've got two big ones coming up against Munster and Leinster. They're big fixtures and there's no rest now. It's tough going.
"Qualifying (for the Amlin Challenge Cup quarter-finals) is not in our hands but there's still three games to go, and you have to stay positive.
"It knocks the stuffing out of you on nights like we had in Harlequins, but we have to stay positive - it's a home fixture for us, we know the opposition, and it's a quick turnaround.
"We know we are capable of beating Harlequins. The last day out we asked enough questions of them, we stopped them playing their game, and we played well in attack. We will continue to play like that again on Friday."
Tickets for Friday's match at the Sportsground are available to purchase here.
CONNACHT (v Harlequins): Gavin Duffy; Darragh Fanning, Ian Keatley, Keith Matthews, Fionn Carr; Miah Nikora, Frank Murphy; Ronan Loughney, Sean Cronin, Jamie Hagan, Michael Swift, Mike McCarthy, Andrew Browne, Johnny O'Connor, John Muldoon (capt).
Replacements: Adrian Flavin, Rob Sweeney, Barry Fa'amausili, Bernie Upton, Mike McComish, Cillian Willis, Troy Nathan, Brian Tuohy.