And with Mercedes team-mate and chief title rival George Russell finishing outside the points in 12th after a late drive-through penalty compounded a troubled weekend, the 19-year-old Antonelli now leads the Drivers' Championship by 66 points after six rounds of what stands as a 22-race campaign.
Hamilton moves ahead of Russell into second in the standings after the Ferrari driver finished second to Antonelli for the second race running.
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Hamilton and team-mate Charles Leclerc both jumped a powerless Max Verstappen immediately at the start - the Dutchman's Red Bull quickly hitting race-ending engine problems from the front row - to run second and third, but they could not keep up with the flying Antonelli from pole.
The Italian led by almost 30 seconds before the first of two late-race Safety Cars for separate crashes at the street circuit's final corner and the race was ultimately suspended so officials could complete track repairs.
Lance Stroll was first to crash at the final turn before home hero Leclerc did the same, just as the condensed field was gearing up to restart.
The racing eventually resumed 40 minutes later for the grand prix's final eight laps, with a second standing start from the grid.
Again, Antonelli made no mistake at the lights - with Hamilton this time next to him on the front row - to ensure his first victory in F1's most legendary race at just the second attempt.
"You can be in no doubt you are looking at a generational talent in Formula 1," declared Sky Sports F1's Martin Brundle.
On a day when an unusually high number of drivers - including Hamilton and Russell - were handed five-second penalties for pit-lane speeding offences, Alpine's Pierre Gasly dropped out of what would have been a stunning third due to two such sanctions being applied to his final race time.
A "heartbroken" Gasly was instead classified seventh and his team later lodged a right of review with the FIA to challenge the costly penalty ruling.
Gasly's penalties promoted countryman Isack Hadjar to the podium for the first time since his winter arrival at Red Bull, a result the Frenchman kept after being cleared in a post-race investigation over an alleged rules infringement under the red flag.
McLaren's difficult weekend ended with a somewhat-flattering fourth place with Oscar Piastri but world champion team-mate Lando Norris, last year's Monaco victor, suffered a second technical race retirement in a row.
With usual front-runners Russell, Leclerc, Norris and Verstappen all failing to score, Racing Bulls cashed in for their best points haul since 2021 as Liam Lawson equalled the best result of his career with fifth and British rookie Arvid Lindblad took his hitherto-highest finish in sixth.
Alex Albon was eighth for Williams ahead of Haas' Esteban Ocon, in ninth.
Sergio Perez crossed the line in 10th for what the new Cadillac team hoped would be their first point in F1 but it was later taken away through a five-second penalty for jumping the second race start.
Aston Martin are instead off the mark for 2026 with Fernando Alonso promoted to the final points-paying place.
How flawless Antonelli mastered Monaco in a league of his own
If the narrow, barrier-lined Monaco circuit serves as the ultimate test of a driver's speed and precision in qualifying, and then for a driver's concentration levels across the 78 racing laps, Antonelli passed both tests with flying colours.
While Verstappen's failure to get away from second place on the front row certainly helped Antonelli's cause to ensure a Mercedes driver finally converted pole position into a first-lap lead this season, the Italian made no mistakes with his own getaway - and then quickly unleashed prodigious pace.
The Monaco GP is often about tyre conservation at the front before drivers eventually push in the lead up to the usual single round of pit stops, but Antonelli ripped up that convention by blasting away from the Ferraris immediately.
He was four seconds ahead of Hamilton by lap five and, while the seven-time world champion briefly came back at him to suggest there might yet be a battle for the win as the race developed, Antonelli's lead was up beyond 12 seconds by the time the lead Ferrari pitted first on lap 29.
"It's unbelievable what he's able to deliver," said Mercedes boss Toto Wolff afterwards.
"Having control, he's at times 1.5 seconds quicker than anyone else."
Antonelli's lead stood at a staggering near-30s by lap 60 when the Safety Car was first called, when Stroll found the barriers at Antony Noghes.
It meant Antonelli's big lead was, at a stroke, wiped out and when Leclerc crashed at the same point as Stroll just as the field was about to restart from behind the Safety Car, a subsequent red flag so officials could inspect the track surface at that problematic corner meant the race would be fully reset by a second start from the grid.
After a 40-minute delay and then two laps behind the Safety Car for refamiliarisation, Antonelli took up the pole position spot once again, although with Hamilton in a hitherto fast-starting Ferrari now alongside him.
Yet, as at the original start some two hours before, the Mercedes driver held his nerve to lead again into Ste Devote. He then swiftly underlined his dominance of the entire afternoon by pulling a six-second lead over Hamilton in the space of just eight laps to take the chequered flag.
"It's been an incredible weekend, an incredible race," said Antonelli, who became the youngest winner of F1's most-prestigious race.
"It was one of those days we had incredible pace. It was all so natural.
"The car was feeling incredible and giving me the confidence to push. It was a very enjoyable day."
Where now for Russell after double penalty jeopardy?
For Mercedes' other driver, an already-difficult weekend in Monaco ultimately unravelled badly.
Two weeks after the heartache of retiring from the lead in Canada due to an engine problem, which not only guaranteed Antonelli another win but meant the Italian increased his title lead by a maximum 25 points, Russell had said he was "bamboozled" by his deficit to his team-mate in qualifying.
His race from the third row was always going to be one of damage limitation with overtaking opportunities around the street circuit famously scarce but Russell was nonetheless running fourth after his first pit stop thanks to Verstappen's early demise and then Mercedes' successful undercutting of Hadjar.
Russell became one of a number of drivers to be handed a five-second sanction for speeding in the pit lane, a penalty which looked likely to be added to his final race time given no more pit stops were expected.
But the appearance of the Stroll-triggered Safety Car meant most drivers ended up unexpectedly pitting for a second time, with F1's rules dictating that Russell should have served his sanction when he arrived in his pit box before the Mercedes crew started work on the car.
However, Mercedes started the car's tyre change immediately, a rules transgression that saw Russell face a fresh in-race investigation.
Stewards ultimately clamped down hard on this indiscretion, handing Russell a more severe drive-through penalty, which he had to serve by coming into the pit lane within three laps of its issuing once the race resumed.
He was by now running third after Leclerc's crash but the extra visit to the pits at a time when the whole field was bunched up meant he tumbled all the way down to a point-less 12th place in the final classification.
Russell told Sky Sports F1: "Five seconds, not ideal but not the end of the world. And then in the pit stop, just major confusion, and getting a drive-through (penalty) - the punishment doesn't fit the crime. So, P3 down to P14.
"I don't really know what to say. It's two races in a row - could have won the race last week, could have maybe been P3-P4 today, it's 40 points down the drain for things outside of my control."
Now down to third in the world championship standings behind former team-mate Hamilton, Russell's deficit to Antonelli is 68 points - the equivalent of two race wins and one second place.
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