"I've never found it easy to have one-night stands ... it tears away at your soul," the Grey's Anatomy and Made of Honor star, 42, tells the U.K. edition of Glamour" magazine for June. "By the time you open yourself up, you have to close yourself off."
Dempsey credits his spouse, a hairdresser now consulting for Avon, with turning around his life after years of losing out on roles, partly because his dyslexia made it difficult to learn lines for auditions.
Together, they bought a farm in Maine, his home state, and Dempsey says he realized, "I could be happy with a different life." His career took off when he developed that perspective.
The actor credits his McDreamy label to the "really good chemistry" between himself and Grey's costar Ellen Pompeo.
"I could just look at her and feel completely emotionally present and unaware of the camera," he says.
He also acknowledges that his status as a small-screen icon added pressure upon his marriage (last year Jillian gave birth to twin boys), but says: "Our relationship is stronger than ever because we know the difference between what is fantasy and what is real. We are in our 40s, not our 20s. We're not caught up in that whole McDreamy thing."
In terms of career, Dempsey sees parallels between his and that of George Clooney's, "someone I respect immensely and get compared to a lot. He is extremely kind about that. We've both played doctors and are both late developers."