The grand finale Senior race was due to take place on Friday and run over four laps, but a fatal incident in the Sidecar race before it and bad weather led to it being postponed to Saturday morning.
Getting underway at 11am local time and the full six-lap distance restored, Harrison came out of the blocks swinging on the opening lap on his DAO Racing Kawasaki fitted with Metzeler slicks.
The defending Senior TT winner from 2019 took a 0.5-second lead over Hickman on the run through Glen Helen, but by Ballaugh the pair had traded places.
Hickman moved 2.4s clear on his FHO Racing BMW, extending that lead to 8.3s come the end of the opening lap.
Harrison – who struck a bird on the first tour and damaged his front fairing - wouldn’t get any closer to Hickman over the second lap, his disadvantage growing to 14.6s as the first round of pitstops took place at the end lap two.
Hickman’s team did cede 3.2s to Harrison’s at the pitstop, with the latter only 10.4s behind at Glen Helen on lap three.
The gap came down again to 9.8s at Ballaugh, but Hickman opened that up again across the rest of the lap to start the fourth tour 18.6s clear.
Come the second round of stops at the end of lap four, Hickman was 19.3s clear – but was 13.9s ahead come Glen Helen on the next tour.
Harrison found a further second on the run to Ballaugh, but again Hickman rallied on his BMW to lead by 16.5s as he began the last lap of TT 2022.
At Glen Helen on lap six, Hickman was 13.9s clear of Harrison, and 12.3s ahead of Ballaugh as the DAO Racing rider tried everything to mount a challenge for victory.
Harrison found two more tenths into the Ramsey sector split, but Hickman kept his pace controlled over the remainder of the lap to become just the third rider in TT history to win four races in a week by 16.9s.
The battle for third raged throughout the six-lap race between Padgetts Racing team-mates Conor Cummins and Davey Todd.
The Honda-mounted duo swapped positions on the timesheets several times, with just a tenth splitting them at the start of the last lap.
But Manxman Cummins dug deep to swell the gap to over two seconds over the mountain and held onto a popular third over Todd by 2.8s.
Supersport winner Michael Dunlop was 1m42s behind Todd in fifth on his Hawk Racing Suzuki, with James Hillier (OMG Racing Yamaha) and Ian Hutchinson on his SMR BMW following him on the timesheets.
Jamie Coward took an impressive eighth on his KTS Racing Yamaha, with John McGuinness ninth after being hit with a 30s pitlane speeding penalty on what could turn out to be his final TT start. Phillip Crowe completed the top 10.
Impressive Honda rookie Glenn Irwin was a retirement at the end of lap four with a bike issue, while Ashcourt Racing’s Lee Johnston was a non-starter.