Whetton, whose father Gary and uncle Alan were stalwart All Blacks locks, will replace Pari Pari Parkinson in the second row as the Highlanders look to end to the Crusaders' 19-match unbeaten streak.
The 26-year-old made his Super Rugby debut for Australia's ACT Brumbies in 2014 but spent four years playing in Europe before returning to New Zealand last season.
He might have hoped for an easier transition back into the provincial competition than a match against the nine-times champions, who have been in dominant form this season and last lost in the corresponding fixture last year.
Parkinson and Thomas Umaga-Jensen both suffered concussions in last week's narrow loss to the Wellington Hurricanes and Teihorangi Walden starts in the centres in place of the latter, while Shannon Frizell comes into the pack at blindside flanker.
The Crusaders, who lead the New Zealand conference with a perfect 4-0 record, welcome captain Sam Whitelock back to their already All Blacks-laden pack for his first game of the season.
Whitelock will line up in the second row with in-form test lock Scott Barrett, while test prop Owen Franks and flanker Matt Todd return after being rested for the nine-try demolition of the Chiefs last week.
Tighthead Franks will be playing his 150th match for the Crusaders in the highly-anticipated clash under the roof of the Otago Stadium.
The second-placed Hurricanes (3-1) take on the Waikato Chiefs (0-4) in Hamilton on Friday having made four changes to the side that beat the Highlanders (2-2), including Wes Goosen replacing prolific winger Ben Lam, who has been rested.
The Chiefs, who have made the playoffs for the last seven years but are enduring a miserable start to the season, made six changes. Those included moving All Blacks livewire Damian McKenzie to fullback with his brother Marty returning from injury to replace him at flyhalf.
The Auckland Blues (1-3) have a bye this week.
(Reporting by Nick Mulvenney in Sydney, editing by Peter Rutherford)
