The stoppage came at 4 minutes, 11 seconds of Round 3.
Gane (10-0), one of the top up-and-coming fighters in the UFC, became the first French-born fighter to win UFC gold.
Lewis (25-8, 1 NC) entered on a four-fight winning streak. He is the all-time UFC heavyweight leader in knockouts (12), a mark that has him tied with Vitor Belfort and Matt Brown for the most ever in UFC history in any weight division.
Lewis, 36, fell in his other title chance, a second-round submission defeat against Daniel Cormier for the undisputed title at UFC 230 in November 2018.
Ciryl Gane dominates Derrick Lewis by third-round TKO to win UFC interim heavyweight title
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