Pogačar buried the field on the long Monte Sante Marie sector, 50 kilometres out from the finish line, and gained more ground despite the steep gradients, tarmac and headwinds.
The Tour de France champion led by as much as 1:40 at one point and left Carlos Rodriguez (Ineos Grenadiers), among other race favourites, with little choice but to settle into a larger chase group.
Three steep sectors situated at the latter portion of the race did reduce Pogačar's advantage, however, but the 23-year-old remained unscathed; entering Siena with a minute in hand on his way to the Piazza del Campo.
Alejandro Valverde of Team Movistar was next to cross the line, followed by Kasper Asgreen who was dropped moments earlier on the Santa Caterina.
Asgreen became Quick-Step Alpha Vinyl's race leader midway through the race after a mass crash caused by the wind with 100 kilometres to go forced Julian Alaphilippe off the road.
Lotto Soudal's Tim Wellens was originally riding alongside Valverde and Asgreen but could not keep pace on the penultimate sector, eventually settling for eighth place.
Instead, it was Attila Valter (Groupama-FDJ) who finished fourth, followed by Pello Bilbao (Bahrain Victorious), Jhonatan Narvaez Prado (Ineos Grenadiers) and Quinn Simmons (Trek-Segafredo).
It was on the fast gravel descent where Pogačar decided to make his move, and the huge risk paid instant dividends - his fellow rivals unwilling to dive down Monte Sante Marie's unforgiving gravel sector.
Pogačar's attack made him the first man in Strade Bianche history to take solo victory after attacking earlier than the 20-kilometre mark, and the Slovenian was "super happy" to get the job done.
"Someone has to be the first someday, no?" he said of his unprecedented attack.
"Sometimes the winners goes at 50 kilometres to go, sometimes at 10 kilometres to go, sometimes in a sprint at the end. You never know what can happen."
"Normally there's a moment when the race goes and this time, I tried to do my best effort on the Sante Marie climb," he added.
"Nobody followed and in the end I was alone. I had to be fully committed when I started so I'm happy that I could do it."
