Whittaker became the first undisputed UFC champion from Australia when Canadian Georges St-Pierre vacated the middleweight title in December.
Whittaker, 27, tried to remain on the event but was ruled medically unable to compete by physicians.
The nature and extent of his injuries is unclear, but the show will go on.
The man Whittaker beat to earn interim gold last summer, Yoel Romero, will take his place.
Winter storm watch issued for this weekend
Today - Rain and sleet before 1 p.m., then freezing rain and sleet between 1 and 2 p.m., then snow and sleet after 2 p.m. Friday for parts of northern and northeastern Arkansas as rain is expected to change to freezing rain and sleet .
"I'm beyond disappointed that I'm unable to defend the title in my home country of Australia", Whittaker said in the release. The new main event at UFC 221 will still have championship gold resting in the balance as Rockhold vs. Romero will fight for an interim strap with the victor facing Whittaker in a unification bout later in 2018. Rockhold and Romero both have great track records in the UFC, and certainly, deserve this headlining spot after the injury bug struck Whittaker. Romero was set to fight against David Branch at UFC Orlando on February 24, he will now fight two weeks earlier than expected, this time for the interim-title. It wasn't meant to be as ESPN brought word of an injury to Whittaker, which has forced him off the card.
"All I can do is focus on getting healthy to come back better than ever". All the best to Yoel and Luke for their fight and ill be waiting...
UFC Fight Night in Orlando is scheduled for February 24, with the first fights at 3:30 p.m. and the main events on the Fox network (WOFL-35 locally) beginning at 8 p.m.
Whittaker (19-4) has gone 7-0 since moving up to the 185-pound division in 2014 after competing at welterweight for the first five years of his career. It was the former champ's first fight since losing his middleweight belt to Bisping at UFC 199 in June of 2016.