Pogacar topped the podium by 1min 24sec ahead of second-placed Briton Tom Pidcock, with Belgium's Tim Wellens a further 48sec adrift.
After victory in the Tuscan one-day race in 2022 and 2024, 26-year-old Pogacar now equals Swiss rider Fabian Cancellara's record of three victories in the Strade Bianche.
"Pretty good race today. The race was super fast. It was a really strong breakaway and our guys did super amazing work in the front," said Pogacar who completed the 213-km race in 5hrs 13mins and 58secs.
"We just went fast and it was a really hard race."
After falling off his bike at a corner on a descent, Pogacar displayed several cuts to his body with blood notably visible on his left shoulder.
"I enjoyed it until I crossed the finish line. Now I'm in adrenaline wear-off and I start to feel a lot of pain," he said.
"Not the best way to win a race, but a win is a win. Let's hope it's nothing worse than it looks and all should be fine."