The Frenchman, who last year won the Fleche Wallonne and Clasica San Sebastian, beat Dane Jakob Fuglsang after an uphill sprint finish at the end of a 184-km ride around Siena peppered with gravelled road sections.
The finish: See how Alaphilippe claimed Strade Bianche crown
"I'm just so happy, my team did a great job today. I knew it was a good race for me," said Alaphilippe, who gave Belgian team Deceuninck-Quick Step their fourth consecutive win in the 2019 classics after they claimed the Het Nieuwsblad, Kuurne-Bruxelles-Kuurne and Le Samyn.
I just had to make no mistake and I made none, I was in a good day. It was my first big goal of the season.
Last year, he ended world champion Alejandro Valverde's four-year reign at the Fleche Wallonne and he is now hungry for more.
"I want to win every race that I start with a winning chance," said Alaphilippe, who has two Tour de France stages to his name and last year won the race's mountain classification.
Alaphilippe is one of France's top young riders.