Weepu replaces Gareth Anscombe in the No10 jersey for the Blues, with Alby Mathewson starting at halfback.
Ma'a Nonu will also come up against his former team for the first time and starts outside Weepu at second-five.
Blues coach Pat Lam has been forced to dip into his wider training group stocks to cover his injury-hit squad.
Liaki Moli will play his first game for the Blues when starting at lock ahead of Anthony Boric, who has a neck injury. Wider training group player James Parsons will cover for Keven Mealamu (calf) on the reserves bench, with Tom McCartney starting.
With Luke Braid hit with a three-week suspension, Chris Lowrey starts at blindside flanker and Brad Mika is No8. Daniel Braid will captain the team from the openside flank.
It was revealed today that back Isaia Toeava's hip injury is worse than first thought and he could miss the rest of the season. Already ruled out for the season is loose forward Jerome Kaino, with a shoulder injury.
Wing George Moala also has a shoulder injury, while fellow outside back Rene Ranger is serving the second game of a two-week suspension.
Some good news for Lam is the return of Tony Woodcock at loosehead prop. Woodcock has sat out the opening four games of the Blues' season to recover from niggling injuries.
Wings Rudi Wulf and David Raikuna are back from injury and will start the match.
Anscombe suffered a nose fracture during last week's defeat by the Stormers but is on the bench.
Blues: Lachie Munro, David Raikuna, Benson Stanley, Ma'a Nonu, rudi Wulf, Piri Weepu, Alby Mathewson, Brad Mika, Daniel Braid (c), Chris Lowrey, Ali Williams, Liaki Moli, Charlie Faumuina, Tom McCartney, Tony Woodcock. Reserves: James Parsons, Tevita Mailau, Filo Paulo, Sean Polwart, Gareth Anscombe, Michael Hobbs, Hadleigh Parkes.
