Now, the 50-year-old actor is trying to find out what his next act might be.
“’Grey’s Anatomy’ was a remarkable ride and without that success I probably wouldn’t be here today talking to you,” he told “Nightline.”
Dempsey came back to his hometown of Lewiston, Maine, after a whirlwind year, which included the dramatic and sudden end of his 11-year run on "Grey’s Anatomy." Fans were shocked when his character, neurosurgeon Dr. Derek Shepherd, was killed off.
“I think everybody was sort of surprised at how abrupt it was,” he said, referring to his character’s demise. “[But] it was time for us both to be finished…it's hard to keep the creative energy going for 10 years.”
In response to reports that he had been a diva on set, Dempsey said, “I can understand why people would say that.”
He continued, “It’s interesting. I think you can never really judge an actor on set, because depending on the dynamic of the scene, you are asked to plug into an emotion.”
To this day, Dempsey said he has never watched that final episode from Season 11 when his character dies after a tragic car accident.
“I haven't seen the final episode. I think it doesn’t end well,” he said, laughing. “One door closes, another door opens, my old man used to say.”
This year, Dempsey also dealt with rumors of divorce after separating from his wife of 17 years (they are back together now). He says things are good at home with his wife and three kids -- the rumors about having another baby aren’t true, he attests -- and that he has been slowing down to focus on family.
“I knew I had to do something because everybody was like, ‘Well he's done, you know, your career is finished. He's retiring, he's not acting anymore.’ And that wasn’t at all the case. I love acting,” Dempsey said.
Long before he was known as “McDreamy,” Dempsey said he had a completely different nickname growing up in Lewiston.
“I was really a small guy growing up and so I was ‘the amoeba.’ That was my nickname,” he said. “It's not your normal nickname. But I was a late-bloomer.”
When he was a teenager, Dempsey, an avid juggler, said he wanted to escape his old mill town to join the Ringling Bros. Circus.
“But I was a bit too young,” he said. “They wouldn’t let me in.”
As for his acting career, Dempsey said he’s ready to take on something new.
“Right now I’m being very cautious in what I ... not cautious, but I’m just trying to be careful in what I do next,” he said.
Though, he said, he will never get tired of being called “McDreamy.”
“It's going to be there for the rest of my life so I have to accept that as a fact,” Dempsey said. “The question will be, will I be known for anything other than that later in life, and that’s the question.”
Watch the full episode on ABC News' "Nightline" TONIGHT at 12:35 a.m. ET.