The Skerries man, who finished second in the class in 2020 behind fellow southern Irishman Derek Sheils, put down a marker with a lap in 1m 25.970s on Friday to secure the top spot from Mike Browne (Burrows Engineering/RK Racing Suzuki) by 1.7s.
Tobermore’s Adam McLean slotted into third on the McAdoo Racing Kawasaki at his home meeting and later sealed pole in the Supersport and Supertwin classes.
Sweeney said: “We got the big bike back to where we wanted it and we haven’t changed a thing with it since we had a test day at Kirkistown earlier this year.
“It’s working well and last year the bike was brand new when I rode it at Cookstown, so we’ve done a lot of mileage on it this year.
“It’s going to be hot to trot if it’s dry especially, and you’ve got Adam McLean, Paul Jordan and Mike Browne – the list goes on – so it’s going to be competitive.
“As long as everyone gets it over safe then that’s the main thing and I’d say we can look forward to the road racing coming back full whack next year, all being well.”
Paul Jordan from Magherafelt, riding for Isle of Man team Prez Racing, was fourth fastest as he made his debut on the team’s 1000cc Yamaha after parting company from the Burrows Racing outfit following the Armoy Road Races in July.
Banbridge native Shaun Anderson (NW Racing BMW) was fifth quickest.
Ulster rider McLean had a successful year in 2020 at Cookstown and the 25-year-old will line up as the favourite for a repeat of his Supersport victory after leading the way on the McAdoo Kawasaki.
He set a hot pace from the front with clear road ahead of him around the 2.1-mile Orritor course, clocking the fastest lap in 1m 26.088s.
McLean’s benchmark put him 0.941s ahead of Cork rider Browne on the Burrows Engineering/RK Racing Yamaha, who was narrowly in front of Jordan (PreZ Racing Yamaha) by 0.087s in third.
Superbike pole man Sweeney was fourth quickest on his Yamaha R6 ahead of Ballymoney’s Darryl Tweed on Stanley Stewart’s Yamaha, who is back in action after a crash at Armoy at the end of July.
McLean also clinched pole in the Supertwin class by 1.1s from Sweeney, with Tweed (McAdoo Kawasaki) third.
In the Moto3/SS300 class, Browne (Joey’s Bar Honda) edged out Enniskillen’s Melissa Kennedy for pole by 0.024s, with Nigel Moore in third 2.5s back.
Tweed led the way in the Lightweight Supersport session while Michael Gillan was quickest in the Junior Supports from RJ Woolsey.
Barry Sheehan from Duleek topped the times in the Senior Support class on his 600cc Yamaha from Offaly’s Keelim Ryan.
In the Classics, Andy Hornby took pole for in the Senior class from Richard Ford, with Barry Davidson fastest of the Junior machines.
Despite a series of red flag stoppages, the Cookstown Club completed a busy practice schedule and also managed to run three support races on Friday.
English rider Dan Harrison won the Open B race on his 600 Yamaha, while Dennis Booth from Ballymena triumphed in the Supersport B race.
Nigel Rea from England won the Senior Support B race on his 600 Suzuki.
The Cookstown 100, postponed from April as a result of the Covid-19 pandemic, is the final Irish national road race of the year.