Jared Payne, who qualifies for Ireland later this year, plays opposite O'Driscoll at centre for the Leinster game following his return from suspension.
Payne has been widely touted as O'Driscoll's replacement for the national side and the New Zealander has previously expressed his interest in playing for Ireland.
Ireland coach Joe Schmidt said after the Six Nations championship victory, he was keeping an eye on the 28-year-old and would consider him in the future.
Elsewhere, talisman Ruan Pienaar misses the game through injury against the league leaders.
Other changes to the line-up from the loss to Glasgow Warriors two weeks ago include Andrew Warwick at tighthead and Roger Wilson, returning from injury, in the back row.
Ireland caps Paul Marshall, Paddy Jackson and Luke Marshall will play inside Payne, with Tommy Bowe, Andrew Trimble and Ricky Andrew continuing in the back three.
Warwick will be joined in the front row by hooker Rob Herring and Tom Court, who will play possibly his last match for Ulster at Ravenhill.
Retiring captain Johann Muller, who will find himself in a similar situation to Court on Friday evening, is again joined in the engine room by Iain Henderson.
Muller, who is likely to make his final Ravenhill appearance on Friday night after announcing his intentions to retire, was keen to thank the Ulster support for helping to make his time in the province so memorable.
He told ulsterrugby.com: "It is no secret that the last four years are possibly the best of my rugby career.
"I have just enjoyed it so much. My family has been so happy in Belfast and the people of Northern Ireland have been absolutely outstanding to us.
"We have loved it here."
Wilson's inclusion at blindside flanker means Chris Henry will switch to the other side of the scrum, while Nick Williams will remain at the base.
International second row Dan Tuohy has returned from injury and is named among the replacements.
Niall Annett, Callum Black and Adam Macklin provide front row support on the bench, with Sean Doyle covering the back row.
Michael Heaney, James McKinney and Darren Cave are selected as backline substitutes.
Ryan Andrew, Andrew Trimble, Jared Payne, Luke Marshall, Tommy Bowe, Paddy Jackson, Paul Marshall, Tom Court, Rob Herring, Andrew Warwick, Johann Muller (captain), Iain Henderson, Roger Wilson, Chris Henry, Nick Williams.
Replacements: Niall Annett, Callum Black, Adam Macklin, Dan Tuohy, Sean Doyle, Michael Heaney, James McKinney, Darren Cave.
Rob Kearney, Zane Kirchner, Brian O'Driscoll, Gordon D'Arcy, Dave Kearney, Ian Madigan, Isaac Boss, Cian Healy, Sean Cronin, Martin Moore, Devin Toner, Mike McCarthy, Rhys Ruddock, Shane Jennings, Jamie Heaslip (captain).
Replacements: Richardt Strauss, Jack McGrath, Mike Ross, Leo Cullen, Jordi Murphy, Luke McGrath, Jimmy Gopperth, Luke Fitzgerald.