A day after breaking the all-time record for pole positions, Hamilton was in total control at Monza, leading team-mate Valtteri Bottas to a one-two.
Ferrari's Sebastian Vettel was third and is three points behind Hamilton.
It is a crucial milestone for Hamilton as F1 next heads to Singapore, where Ferrari are expected to dominate.
The victory was Hamilton's sixth of the season - Vettel has only four - and it capped a perfect weekend for him.
He scored a brilliant pole in treacherous wet conditions on Saturday - more than a second clear of the next fastest driver - to take his tally to 69, one more than Ferrari legend Michael Schumacher.
Hamilton's victory was among the most straightforward of the season. He fought off a brief challenge from Williams driver Lance Stroll, a remarkable second on the grid, on the run down to the first corner and disappeared into a race of his own.
"The team did an amazing job. Valtteri did a great job. Mercedes power is better than Ferrari power so that's one thing," Hamilton said, as he was booed by the Tifosi during the podium interviews.
The fight was all behind him, as Bottas and the Ferrari drivers set about fighting up from their unusually low grid positions.
The Finn, who started sixth, was up to fourth on the first lap behind Hamilton, Force India's Esteban Ocon, another star of qualifying, and Stroll, who dropped a place in a tussle at the first corner.
Bottas got Stroll into Turn One on lap three, Ocon in the same place a lap later, to give Mercedes total control of the race, which they never surrendered.
Vettel limited the damage to his title hopes as much as was possible in the circumstances, passing team-mate Kimi Raikkonen around the outside into the first Lesmo on lap three, Stroll a couple of laps later before picking off Ocon into Turn One on lap eight.
The German, though, was no match for the Mercedes at Ferrari's home race - generally dropping at least half a second a lap - and his focus in the second part of the race became holding off Red Bull's Daniel Ricciardo.
The Australian, who qualified third but started 16th after being given a grid penalty for using too many engine parts this season, put in a brilliant recovery from his lowly grid position.
He picked his way through the slower cars in the first part of the race, pulling off a series of his trademark aggressive overtaking moves, and ran a long first stint to give himself fresher tyres for the final stint than the Ferraris ahead of him.
Ricciardo dived brilliantly inside Raikkonen from a long way back at the first chicane with 12 laps to go and began to set off after Vettel, who was just over 11 seconds ahead.
Initially, he began to close at a second a lap, but as the edge went from his tyres, his advantage reduced and Vettel crossed the line four seconds ahead.
Vettel later told his team over the radio that he had gone off track at one point and felt "something was wrong" afterwards, explaining part of his lack of pace.
"My start was not so good - I had quite a lot of wheel spin and we didn't quite have the pace of the leading two cars but seeing the people and having that support was amazing," Vettel said afterwards.
"We have a very strong car and will have a very strong end of the season."
Ricciardo's team-mate Max Verstappen got up from 13th on the grid - also victim of a penalty after qualifying second in the wet - to be eighth on the first lap.
But he wrecked his race by tangling with Williams driver Felipe Massa on the second lap, damaging his front wing and getting a puncture and rejoined last.
Verstappen recovered to 10th place, incurring the anger of Haas' Kevin Magnussen, from whom he stole the final point, when he moved over on him while overtaking the Dane at the second chicane and forced him on to the grass.
Stroll and Ocon inevitably slipped back behind faster cars from their superb starting positions, earned with starring drives in the wet.
But both drove solid and strong races to finish sixth and seventh, the Canadian fending off team-mate Felipe Massa for seventh place on the last lap, as the pair also fended off the second Force India of Sergio Perez.
Mercedes' Lewis Hamilton took the outright championship lead for the first time this season with a dominant victory in the Italian Grand Prix.