A day after claiming the lengthy individual time-trial in Perugia, the 25-year-old Team UAE leader paced himself up the 14km final climb along with an elite clique before producing his trademark late kick to the 1,425m altitude finish line in the Abruzzo region.
Pogacar also won the second stage, a summit finish at the Sanctuary of Oropa in Piedmont.
In his bid to win the Giro and Tour de France in the same season he now leads title rivals Dani Martinez by 2min 40sec and Geraint Thomas in third by 2min 58sec with the pair close on his heels on the second mountain stage in the 21-day race.
Australia's AG2R man Ben O'Connor at 3min 39sec and Belgian Visma rider Cian Uijtdebroeks at 4min 02sec round out the top five in the overall standings.
The Slovenian two-time Tour de France champion is taking part in the Giro for the first time and hopes to emulate Italy's Marco Pantani who won the double in 1998.
"My team won this one in a way," said Pogacar, who was paced all the way by team-mate Rafal Majka.
The race continues Sunday with a largely flat 214km stage nine to the southern port city of Naples on a route open to attacks from the same kind of one-day specialists that lit up stage six on the Tuscan gravel.
"Sunday will be easier for us and we could do with some breathing space now," said Pogacar, known for his all-in style and desire to rack up stage wins.
Ineos leader Thomas had a more poised approach to the art of negotiating the 21-day long-haul and said he was more than happy after the climb.
"I felt much better today, it's like night and day," said the veteran, hoping to find his peak in the ultra-mountainous third week.
Thomas was just 2sec adrift on the day after being paced by young team-mate Thymen Arensman.
Dutch outfit Visma lost another of their chief riders to injury when Christophe Laporte failed to show up for the start. He fell hard when hitting a gutter on stage five.
The Visma team are reeling from injuries to double Tour de France champion Jonas Vingegaard and one day expert Wout van Aert.
