Verstappen nailed his launch in slippery conditions following a pre-race shower at Imola to jump rival Leclerc and then he took control of the race with a run of fastest lapse.
With Leclerc also ceding a place to Perez into the opening sequence of corners, Saturday sprint race winner Verstappen did not look under threat as he romped to a win by 16.5s.
Ferrari had rolled the dice with a late pitstop to put Leclerc on the fastest available tire before Red Bull did the same, but as Leclerc attempted to reel in the leaders, he spun before recovering to sixth place.
The full grid opted to start on intermediates, all running a brand-new set of rubber except for Lewis Hamilton, who instead selected a set of scrubbed grooved tires.
Verstappen overcame his wheelspin issues that hampered his sprint getaway by launching cleanly and pulling from the left-side of the grid to cover any potential threat off the line.
But Leclerc was much slower away, allowing Perez to get the jump on the Ferrari for second and then he had to defend from Norris, who squeezed the Ferrari into fourth at Tamburello.
There, Carlos Sainz’s torrid run of form continued as he ended up beached in the gravel after tangling with Daniel Ricciardo through the second part of the chicane.
It appeared as though Ricciardo touched the curb and slid wide to tag Sainz into a spin, the incident passed without investigation. Ricciardo subsequently pitted and resumed down in 18th.
Sainz was then stuck on the outside and duly retired as Mick Schumacher dropped from 10th to 17th after a half-spin, and as his rear-axle slid he tagged the sidepod of Fernando Alonso.
The safety car was eventually called at the end of the opening lap to pick up leader Verstappen, with Perez in second over Norris, Leclerc and Haas driver Kevin Magnussen.
George Russell, meanwhile, enjoyed a lightning launch to progress from 11th into sixth, as the Aston Martins of Sebastian Vettel and Lance Stroll made similar progress to climb four spots.
Verstappen turned down the choice from the pitwall to dive in for slicks and the rest of field stuck to their intermediates despite reports of the track drying.
The safety car pulled in at the end of lap four, and the Red Bulls aced the restart to run away by 1.5s over Norris, who covered off a potential challenge from Leclerc into Tamburello.
It took until lap eight for Leclerc to demote the McLaren. Norris oversteered out of Rivazza to allow Leclerc to latch onto his slipstream and dart past on the inside into Tamburello.
From there, the Ferrari driver had a 6.2s deficit to Verstappen and sat 3.3s adrift of Perez.
Over the next seven tours, those gaps condensed to leave Verstappen in front by 5.5s over his Red Bull teammate as Leclerc sat 1.9s in arrears of Perez.
Verstappen then indicated over team radio that he was ready for slick tires in the event of a safety car but remained on track for the time being as Ricciardo rolled the dice on mediums.
Ricciardo immediately started a run of personal best sector times to indicate the crossover from inters to the yellow-walled C4 Pirellis.
Although the Ferrari crew emerged into the pitlane, Verstappen and Leclerc stayed put as Perez and Russell – who had eventually fought his way past Magnussen at Variante Alta after running deep into Tamburello – were the leading runners to dive in.
Leclerc had clear air to close the 8s gap to Verstappen until next time around, on lap 19, the top two shot into their pit boxes.
Leclerc came out in front of Perez but with the new-for-2022 tire temperature regulations, struggled on the cooler rubber and fell back to third.
Perez, having passed at the Villeneuve chicane, again provided a buffer for Verstappen who stretched the legs of the RB18 to lead by 7.5s.
Leclerc, now with his tires up to temperature, might have ironed Perez for second after the Mexican locked his front-left into Variante Alta and skipped the chicane to hit the grass.
But while Leclerc could close, with DRS still disabled despite the whole field switching to mediums, he could not pass and again settled in behind the Red Bull.
Leclerc had struggled, unlike Verstappen, to manage the graining of the front-right tire in the sprint. Verstappen looked to have retained his superiority as his lead exceeded 10s by lap 32.
The defending champion began to dip into the low 1m20s each lap, running 0.3s quicker than Perez, and even lapping the struggling Mercedes of Hamilton on lap 40.
With Leclerc’s pursuit of Perez fading, Ferrari called him in for a set of softs on lap 50 and he only took one DRS zone to streak past Norris to resume in third place.
Red Bull responded over the next two laps by pitting first Perez and then Verstappen for softs, which brought Leclerc onto Perez’s six.
Leclerc had a seven-tenth gap only to Perez but on lap 53, he clattered the kerbs at the Variante Alta chicane and spun at the outside wall.
He broke an endplate although hit the wall square on to avoid suspension damage, resuming to pit for a new front wing and another set of softs and returned to the track down in ninth place.
That relieved the pressure on the Red Bull as Verstappen who, despite reporting some lap drops of rain, crossed the line to take his second full GP victory of the season, the same tally as Leclerc.
He landed the point for fastest lap to boot.
Perez delivered second place over Norris, who completed the podium another 18.3s behind.
Russell bagged fourth, despite Mercedes not adjusting his front-wing aero balance at his pitstop, but he still came out on top in an entertaining late scrap with Valtteri Bottas.
Leclerc recovered to sixth after a late show of damage limitation to fight past Vettel and Tsunoda, while Magnussen and Stroll completed the top 10.
Alexander Albon’s much improved pace on Sunday for Williams deserved 11th ahead of Gasly, while Hamilton was unable to pass the AlphaTauri despite a protracted chase.
Ocon landed 14th following a five-second penalty for an unsafe release during the switch from inters to slicks, which forced Hamilton to lift off in the pitlane and drop a place.
Zhou was 15th over Nicholas Latifi and Schumacher, who spun for the second time, while Ricciardo stopped for a set of hard tires before rounding out the finishers in 18th.