The Slovenian won his first world road race title in Geneva on September 29 after attacking 100 kilometres from the end. This time he attacked 37km from the finish in Bologna.
"I'm super happy to win this race with the world champion's jersey on my shoulders. I felt great today, whereas in the four days following my title, I was drained," he said.
"As a new world champion, I felt a certain pressure, but it was a great day."
Pogacar finished the 215.8km race 1 minute 54 seconds ahead of Briton Tom Pidcock who edged Italian Davide Piganzoli in a sprint for second.
The race serves as the penultimate warm-up for the last one-day 'monument' of the year, the Tour of Lombardy. Pogacar will ride the Three Valleys of Varese on Tuesday, before trying to win in the 'race of the falling leaves' on Saturday for a fourth straight year.
It was Pogacar's 23rd victory in 56 days of racing this year, a ratio that makes his 2024 season one of the finest in cycling history.
In intermittent rain and fog, the winner of the Tour de France and Giro d'Italia once again left his rivals, including compatriot Primoz Roglic, the defending champion and three-time winner of the event, trailing.
After Remco Evenepoel made the first move. Pogacar chased the Belgian down and then accelerated past and went away on the first of five climbs of the fearsome "Wall of San Luca".
Evenepoel dropped out with 25km to go.
