Adrian Flavin, with 138 senior caps for the province, has been named as hooker and is joined by Finlay Bealham and Rodney Ah You in the all-new front row trio.
Conor Kindregan, who came off the bench last weekend, will combine with David Gannon in the second row.
Flanker Thomas Anderson also made an appearance from the bench in round 3 after his return from injury. He will start at blindside flanker this Saturday alongside captain Eoghan Grace and Aaron Conneely in the back row.
There are no changes to the back-line with the strong centre partnership of Brian Murphy and Tadhg Leader remaining in place for the return fixture which gets underway at 2pm.
"We were very happy with how we played last weekend, especially in the second half," he said.
"We created a lot of opportunities but unfortunately we failed to convert them into scores and the overall outcome was disappointing. This week, we will be focusing on accuracy and making these opportunities count."
Connacht Rugby Season Ticket holders are admitted free of charge to all Connacht Eagles home British & Irish Cup games. Adult tickets at the gate are priced at €10 and children's tickets are €5.
CONNACHT EAGLES (v Cross Keys): James Loxton; Mark McCrea, Tadhg Leader, Brian Murphy, Matt Healy; Jack Carty, David Moore; Finlay Bealham, Adrian Flavin, Rodney Ah You, Conor Kindregan, David Gannon, Thomas Anderson, Eoghan Grace (capt), Aaron Conneely.
Replacements: Kevin O'Byrne, Peter Reilly, Ultan Dillane, David Heffernan, Marcus Walsh, Conor Finn, Finn Gormley.