The 46-year-old actress addressed the 50-year-old actor's departure on Monday's episode of The Ellen DeGeneres Show. Pompeo and Dempsey co-starred as Meredith Grey and Derek Shepherd before the actor left the series after Season 11.
"It's amazing how much you get done without a penis," Pompeo said with a laugh. "We miss him dearly, but yeah, the show is doing very well."
"I think a lot of people were really upset about his departure, which is super understandable, but I think the change is part of the reason why the show goes on so long," she explained. "I think people tune in to see, 'What does the show look like now?'"
"For me, too, it's, 'How do I act without him?'" the star added. "It's more challenging for me. I'm more invested. I have to work harder to find my groove without that missing part, so it keeps me more engaged. I'm more engaged [in Season 12] than I have been in a long time."
Pompeo told fans she was "honored" and "excited" to continue Meredith's story following Derek's death on the Season 11 finale. She later expressed frustration with fixation on Dempsey in the Sept. 11 issue of Entertainment Weekly.
"All of a sudden, Patrick leaves, and it's like, 'Oh my God, Meredith's gonna get killed with Alzheimer's! The show couldn't possibly go on without the man!'" the actress vented.
"It's like, [Viola Davis as] Annalise Keating carries [How to Get Away with Murder], [Kerry Washington as] Olivia Pope carries [Scandal]," she explained. "Why can't I just be the lead of the show the way Annalise and Olivia can? Why can't I be on that poster by myself?"
Grey's Anatomy is in its 12th season and airs Thursdays at 8 p.m. ET on ABC. The medical drama co-stars Justin Chambers, Chandra Wilson and James Pickens, Jr., and was renewed for a 13th season in March.