Whittaker, 27, tried to remain on the event but was ruled medically unable to compete by physicians.
Rockhold (16-3) will now face Yoel Romero (12-2) for an interim 185-pound championship. UFC officials told ESPN that Whittaker will face the winner in a unification bout.
"I'm beyond disappointed that I'm unable to defend the title in my home country of Australia," Whittaker stated. "I hope the fans enjoy what should be a great night of fights at UFC 221, and I look forward to a recovery as soon as possible that will have me back in the Octagon to face the winner of the main event."
It's a major blow to the UFC's 221 pay-per-view event, which is scheduled to take place in Perth, Australia.
Whittaker was an obvious choice to headline the event, as he is the first Australia-based champion in UFC history. Customers who purchased tickets are eligible for a full refund.
Rockhold, who trains out of American Kickboxing Academy and Combat Club, is looking to recapture a UFC title. He won the 185-pound championship in December 2015, but surrendered it to Michael Bisping in his first attempted defense.
The 33-year-old former champion is coming off a TKO win over David Branch in September.
A former Cuban Olympic silver-medalist wrestler, Romero was scheduled to face Branch at a UFC Fight Night event on Feb. 24. He is actually coming off a decision loss to Whittaker for the interim title last July.
The switch is yet another strange turn in the UFC's middleweight division. In November, former welterweight champion Georges St-Pierre returned from a four-year absence to win the title against Bisping at UFC 217. St-Pierre opted to vacate the championship just 31 days later, citing health reasons.