All three judges scored the bout 50-45 for Adesanya.
The fight was a rematch of a 2018 split-decision win for Adesanya, which was one of the most difficult fights in his run to the belt.
ESPN has Adesanya ranked No. 3 on its pound-for-pound men's MMA fighter list. At middleweight, Adesanya is ranked No. 1; Vettori is No. 6.
Adesanya (21-1), 31, made the third successful defense of his middleweight title.