In giving Aaron Smith a bench place, the selectors have taken away the sharpest passing halfback in the land.
Other changes are in the pack where Liam Messam, Sam Whitelock and Andrew Hore start instead of Victor Vito, Brodie Retallick and Keven Mealamu.
Utility back Tamati Ellison has replaced Ben Smith on the bench.
Weepu was one of the stars of the World Cup who took on extra responsibility as the five-eighths injury crisis escalated.
He took over the goal kicking in the latter stages of the tournament as his form surged past long-term rivals Jimmy Cowan and Andy Ellis.
But after that success, Weepu's form tapered as his weight ballooned.
He arrived out of condition at his new Blues franchise, played poorly and was not helped by being picked at halfback and five-eighths.
Weepu was included in several All Black training camps but told his place was in jeopardy if he did not trim down. He listened to the warning and took the advice of trainers and nutritionists. He knuckled down, lost about 10kg and scraped into the squad as the experienced halfback to go with the rookie Smith.
The No 9 jersey eluded him though as he stayed in the reserves for three tests against Ireland, two against the Wallabies and then the Pumas.
Weepu and Aaron Cruden will team up for their third start together after two at the World Cup and the forgettable test in Sydney against the Wallabies in 2010.
Hansen said his crew were obviously happy with results at the halfway stage of the Rugby Championship.
"There is a second challenge we have set ourselves - to constantly improve our game - and in that regard we are not the finished product."
Progress was steady and this test against the Boks was another chance to confront their missions.
Messam's form as a sub last week and comments by Hansen were a strong hint he would start this test ahead of Victor Vito.
The selectors were also encouraged by signs Whitelock had rediscovered his sting and that experience will be needed in for the tight five battle with the Boks.
It's been three on three off shifts for the hookers with Hore starting in June when Mealamu was recovering from his calf troubles and then swapping for the Rugby Championship. Now Hore gets a run on his home track alongside his new Highlanders loosehead prop Tony Woodcock.
Starting XV:
1. Tony Woodcock (88)
2. Andrew Hore (68)
3. Owen Franks (37)
4. Luke Romano (4)
5. Samuel Whitelock (31)
6. Liam Messam (13)
7. Richie McCaw - captain (109)
8. Kieran Read (41)
9. Piri Weepu (62)
10. Aaron Cruden (13)
11. Julian Savea (3)
12. Ma'a Nonu (69)
13. Conrad Smith (59)
14. Cory Jane (34)
15. Israel Dagg (18)
Reserves:
16. Keven Mealamu (96)
17. Charlie Faumuina (1)
18. Brodie Retallick (6)
19. Victor Vito (15)
20. Aaron Smith (6)
21. Beauden Barrett (2)
22. Tamati Ellison (2)