The two-time Tour de France champion made his move on the decisive Passo di Granda climb and crossed the line first in Bergamo, comfortably ahead of a star-studded field of riders.
UAE rider Pogacar joined Alfredo Binda and seven-time Grand Tour champion Fausto Coppi, a winner four times between 1946 and 1949, to complete the streak of wins in the "Race of the Falling Leaves".
It was another big victory in a year in which Pogacar finished second in the Tour and claimed the honours in Paris-Nice, the Fleche Wallonne, the Tour of Flanders and the Amstel Gold Race.
"In the moment that I got a little gap, I knew the descent a little better than two years ago when it was a bit of a disaster for me, but today I gave it my all and it was tough to go so far to the finish," said Pogacar.
The Slovenian, 25, finished nearly a minute ahead of the chasing pack, capping another eventful year with triumph in the gruelling 238-kilometre race which contained a series of punishing climbs.
He cruised to victory despite picking up cramp in both his legs soon after reaching the plain between the decisive Passo di Granda and the punchy Colle Aperto which leads into Bergamo.
"I was thinking that was it, but I pushed through and I lowered down the power and focused on being as aero as possible to save myself for the final kick," he added.
"To win the third time at my third participation, second here in Bergamo, it's a dream to come solo and today it was fantastic. I was enjoying the last few kilometres even though it was so painful."
Pogacar saw off a field which included compatriot and reigning Giro d'Italia champion Primoz Roglic, who couldn't pull off a win in his last race before leaving Jumbo-Visma for Bora-Hansgrohe.
Pinot's farewell
Roglic was among a clutch of riders including world time-trial champion Remco Evenepoel, Adam Yates and Julian Alaphilippe who had hopes of glory in northern Italy but could do nothing to stop Pogacar.
French rider Thibaut Pinot also said goodbye in his final race as a professional road cyclist, one attended by an impressive number of French fans who crossed the Alps in the vain hope that their hero could repeat his 2018 victory.
"I might not be world champion but I have the best fans in the world. It's been a wonderful experience," said Pinot.
"I knew it was going to be a difficult day and that's what it turned out to be. But I kept fighting because I knew I had to finish."
The first few hours of the race were fairly uneventful beyond a couple of breaks which were caught by Ben Healy and Oscar Onley just before the Zambla Alta climb with 70km to go.
Healy pushed the nine-man break over the 10km ascent as the star-studded peloton lurked just over a minute behind, before he and Martin Marcellusi drew ahead of the rest before the winding Passo di Granda climb.
However the Irishman was caught after Pogacar's teammate Yates attacked from the peloton, and Pogacar and Roglic both worked their way into the leading group of 11, setting up what looked to be a battle between some of cycling's biggest stars.
But it was Pogacar who suddenly burst in front, and Aleksandr Vlasov lent a hand in keeping the rest of the break off his heels until he decided to go it alone.
He opened up a 30-second gap on the descent and by the time he hit the flat road with 15km left there was enough space between him and the chasers that not even cramp could stop him from victory.
