The Australia ace, one of the Rebels' extended leadership group, takes the captain's armband from Wales No8 Delve, who has suffered a shoulder injury.
There are no long-term concerns over Delve but boss Damien Hill reckons O'Connor has developed the maturity to lead the franchise in the former Bath and Gloucester backrower's absence.
"Nothing is structurally wrong with Gareth's shoulder. He took a beating last week and simply has not recovered in time for this week's match," said coach Hill.
"James has really matured over the past six months as a footballer, and was humbled by the opportunity when I presented the captaincy role to him."
The loss of Delve has led to a reshuffle of the Rebels pack. Wallabies regular Scott Higginbotham moves across to No8, with Luke Jones filling in on the flank.
Caderyn Neville starts in the second-row, while Jordy Reid could make his Super Rugby debut from the bench.
"We have spoken about the club's depth this year compared to others, and for the Rebels to be able to replace Delve with Higginbotham, while bringing in Wallaby tourists to the starting team is a demonstration of that," added Hill.
Kurtley Beale has fully recovered from the shoulder injury he picked up in the 30-13 defeat to ACT Brumbies.
The Wallabies star will continue at fly-half, in an unchanged back-line, against his former team.