Hickman led from the first sector split of the opening lap of the six-lap Superbike race and eased to his sixth-career victory at the TT on the all-new BMW M1000RR.
McGuinness led the field from the number one spot to start his 100th TT race aboard his Honda, though sat 11th on the leaderboard through the Glen Helen section.
Setting off a minute later, FHO Racing’s Hickman grabbed the lead through Glen Helen on his BMW M1000RR, ahead of Padgetts Racing’s Davey Todd on the Honda by 3.1 seconds.
Hickman continued to extend his lead over the opening lap as Dean Harrison on the DAO Racing Kawasaki and the sister Padgetts Honda of Connor Cummins swapped second spot on the runs through the Ramsey and Bungalow sectors.
Harrison held onto second as he moved onto the second of six laps, with Hickman leading by 9.3s.
By Glen Helen on the second lap, Hickman had increased his lead to 11.9s, as Todd moved ahead of team-mate Cummins for third.
But Todd’s race wouldn’t last much longer as he retired at the Sulby section when his rear Dunlop tyre delaminated, with team-mate Cummins dropping out of the running somewhere on the mountain descent.
Dunlop has yet to get the tyre back to analyse, but it comes after it elected to withdraw its rear slick allocation ahead of the TT following delamination issues at the North West 200 with a batch of rear slicks.
This pushed Michael Dunlop on his Hawk Racing Suzuki into a comfortable third, as Hickman’s lead over Harrison swelled to 16.8s as the first of the pitstops took place.
Hickman’s lap into the pits was a 133.46mph, with his lead over Harrison into Glen Helen on lap three moving out to 18.1s.
Through the second round of stops at the end of the fourth lap, Hickman’s lead had ballooned to 36s and was out to 40s as he began his final run across the 37.75-mile Mountain Course.
Taking it relatively easy across his final lap, Hickman took the chequered flag 39.199s from Harrison for his third win in the Superbike class at the TT.
Dunlop reeled Harrison to get the gap to under 10s at one stage, but Harrison rebounded to beat the Ulsterman by 18.427s.
Ian Hutchinson was over two minutes further back in fourth on his TAS Racing BMW, with McGuinness completing the top five 10.782s adrift having run in fourth at one stage.
Jamie Coward was an impressive sixth on his KTS Racing BMW ahead of OMG Racing’s James Hillier on his Yamaha, with Honda TT rookie Glenn Irwin stunning on his race debut in eighth – setting the fastest ever lap for a newcomer with a 129.85mph.
Crendon Suzuki’s Shaun Anderson and Dominic Herbertson on his Haith BMW completed the top 10, with TT veteran Michael Rutter (Bathams Racing BMW) 11th.
After an initial strong start to his race, Lee Johnston was another retirement on his Ashcourt Racing BMW, which he was running in Superstock spec.
