A leg injury for Ireland full-back Girvan Dempsey means Leinster will line out with Rob Kearney at full-back and Luke Fitzgerald on the left flank for tomorrow's Liberty Stadium encounter (kick-off 7.10pm).
Leinster will travel with a youthful half-back partnership, with Sexton and scrum half Cillian Willis both 22 years of age.
In the pack, Stan Wright, Leo Cullen and Keith Gleeson remain from last weekend with Cameron Jowitt, who came on as a replacement against Toulouse, forming a new back row unit alongside Kevin McLaughlin and Ireland international Gleeson.
Ireland 'A' hooker Brian Blaney also comes into the starting line-up, while the province's bench includes the likes of Warner, Gary Brown, Ireland internationals Bernard Jackman, Malcolm O'Kelly and Shane Jennings, as well as fit-again Ireland 'A' scrum half Chris Keane.
A decision on replacement prop will be confirmed by the Leinster management closer to kick-off.
Rallying his troops after last week's European loss to Toulouse, Leinster coach Michael Cheika said: "It's not like we're in a losing streak. Our last two performances in the Magners League before the win against Leicester had been good, away to Ulster and then at home to Connacht.
"We're in third place in the league and we want to be as competitive as we possibly can be. This year I'm much happier with the squad's ability to rotate and we will need to be at our best on Friday."
LEINSTER (v Ospreys): Rob Kearney; Shane Horgan, Brian O'Driscoll (capt), Felipe Contepomi, Luke Fitzgerald; Jonathan Sexton, Cillian Willis; Stan Wright, Brian Blaney, Juan Francisco Gomez, Leo Cullen, Devin Toner, Cameron Jowitt, Keith Gleeson, Kevin McLaughlin.
Replacements: Bernard Jackman, Cian Healy/Ollie Le Roux, Malcolm O'Kelly, Shane Jennings, Chris Keane, Christian Warner, Gary Brown.