On the 222 km ride from Manerba del Garda to Livigno, Pogacar attacked on the climb with a 14 km solo ride to chase down the breakaway riders and leader Nairo Quintana, overtaking the Colombian with 1.9 km to go on the Mottolino ascent.
Pogacar then dropped Quintana, a Giro d'Italia winner in 2014 who he had watched race as a child, and the Slovenian raced to the summit, leaving the chasing pack far behind to almost double his overall lead with one week to go.
"Today was one of the best days for me... it was a really nice stage, really good route with nice climbs. The team did a good job. We had this stage in mind since December," Pogacar said.
"I'm super happy that we kept it under control. It was a really strong breakaway but I gave it all in the last 10-15 km. I'm super happy I could win a Queen Stage in Livigno, one of my favourite places in Italy.
"I used to watch Quintana and (Chris) Froome attacking each other but always too close to the finish. I was always angry that he (Quintana) wouldn't attack from distance but today he did a good job."
The victory was Pogacar's fourth stage win and he crossed the line with no rider in sight while his closest rivals Dani Martinez (Bora-Hansgrohe) and Geraint Thomas (Ineos Grenadiers) finished fifth and sixth, two minutes and 51 seconds behind.
Pogacar, a twice winner of the Tour de France, has now established a lead of six minutes and 41 seconds over Thomas while Martinez is a further 15 seconds behind.
Monday is a rest day and the Giro resumes a day later with stage 16 in the mountains, a 202 km ride from Livigno to Santa Cristina Valgardena.
