The 57-year-old actor replaces last year’s titleholder, Marvel’s Captain America star, Chris Evans.
Reacting to the honour, Dempsey said in his cover story for People: “It’s nice to have the recognition, and certainly my ego takes a little bump, but it gives me the platform to use it for something positive.”
He joked that he has “always been the bridesmaid” to the other sexiest men alive and now he gets to be the real thing.
Dempsey played heartthrob neurosurgeon Derek “McDreamy” Shepherd in Grey’s Anatomy.
He made over 250 appearances on the hit medical drama, starring as a main character from 2005 to 2015.
He returned as Dr Shepherd in a recurring role in 2019, before leaving the show for good.
Dempsey also starred in the 2007 Disney blockbuster, Enchanted, and its 2022 sequel, Disenchanted.
He is due to star as the real-life Italian Formula One driver Piero Taruffi in the film Ferrari – a biopic about the life of the carmaker’s founder Enzo Ferrari – which is due to be released next month.
Dempsey is married to makeup artist and beauty line founder Jillian Fink, with whom he has three children, Talula, 21, and 16-year-old twins Sullivan and Darby.
“They’re just going to make fun of me and pick on me and figure out every reason why I shouldn’t be [the sexiest man alive], which is good, they keep me young,” he said of his children.
Other “sexiest man alive” recipients include Black Panther star Michael B. Jordan, singer John Legend, Ant-Man actor Paul Rudd, Brad Pitt, Harrison Ford, and Braveheart’s Mel Gibson – who was the magazine’s first recipient in 1985.