After two attacks left most of his rivals gasping for air, the Slovenian made the decisive move in the descent to Bergamo and never looked back despite suffering from cramps in the final kilometres.
Italian Andrea Bagioli was second with Primoz Roglic coming home third, both 52 seconds off the pace.
Pogacar, who finished second in the Tour de France this year, also won the second Monument of the season, the Tour of Flanders - one of his 17 victories this year.
"Winning here three times in a row is fantastic," Pogacar said.
"I felt very strong today and I knew the final well, so I had to attack far from the finish. I would have preferred to start with (Aleksandr) Vlasov and work with him all the way to the finish, but they soon came back behind me, so on instinct, I accelerated at the start of the descent, got a bit of a lead and that was enough.
"It was another very, very hard day of racing. I was on the verge of cramps in the final. For a moment, I thought it was over."
The GOAT
Pogacar is the third rider to win the Lombardia three times in a row, after Alberto Binda in the 1920s and Fausto Coppi in the 1940s.
Way behind, Pinot, riding the last professional race of his career, was greeted by hundreds of partying fans who made the trip to give France's most beloved rider a superb farewell.
Pinot, who won the Giro di Lombardia in 2018 and finished third in the 2014 Tour de France, smiled as he fended off the sea of flag-waving fans.
The Groupama-FDJ rider, whose career was hampered by injuries, one forcing him to abandon two days before the 2019 Tour, which he was in position to win, heads into retirement to his farm in Eastern France.
An animal lover, Pinot also received a goat named Vittoria as a present from the Giro di Lombardia organisers.
She has already made it to the small town of Melisey, where Pinot will take care of his animals and go fishing in the nearby lake.
