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New Zealand-based, Nigerian-born Adesanya landed a right hook which floored Whittaker in the final seconds of the first round and ended the fight in the second of the five-round contest with a left hook.
In all it took Adesanya 3 minutes 35 seconds.
It was New Zealand-born Australian Whittaker's first fight since June 2018 in Chicago. The 28-year-old Whittaker was scheduled to fight in February but withdrew due to emergency bowel surgery.
In the build-up to the main fight New Zealand fighter Brad Riddell kicked off his UFC career in thrilling fashion with a unanimous decision victory over Australian Jamie Mullarkey.
Another Kiwi Dan Hooker dominated his opponent Al Iaquinta to win in three rounds, while compatriot Luke Jumeau lost his fight to Dhiego Lima.