The 57-year-old actor admitted to feeling the remnants of the Ambien he took after a red-eye flight the night before and smoked several cigarettes while on stage.
Always the candid interviewee, Penn started off his interview by nonchalantly telling Colbert about his Ambien-induced state.
"I'm doing well. You've inherited a little bit of the Ambien I had to take to get to sleep after a red eye last night," he admitted, agreeing with Colbert that he was on the "Ambien train."
"I've interviewed you before. How do you tell Sean Penn on Ambien from Sean Penn not on Ambien?" Colbert quipped. "Because you lay back in interviews in a really big way."
"I think it's pretty much the same," Penn noted, while pulling out a pack of cigarettes and lighting one up. "There's a lot of times I'm just regular tired."
The audience chuckled along while Penn smoked his cigarettes in what turned out to be a bizarre interview promoting his first novel, Bob Honey Who Just Do Stuff, which is about a septic tank salesman-turned-assassin who kills people with a mallet.
The two-time Oscar winner gave Colbert some insight into his recent declaration on CBS This Morning that he plans to step away from acting.
"The greatest thing that an actor can bring to the party is to play well with others – it's the collaboration," Penn explained. "And I increasingly don't play well with others and so it becomes less enjoyable. I love that process when I love it, but I'm not loving that anymore. And that's really why I finally came out to writing a novel."
When finally Colbert asked him to stop smoking cigarettes for the sake of his own health, Penn jokingly replied, "This is job security for oncologists."
Penn ended his interview by praising the Parkland, Florida high school shooting survivors who responded to the Marjory Stoneman Douglas massacre by organizing last weekend's March for Our Lives rally against gun violence.
"Within days of that not only are they stating their case with incredible sobriety and articulate words but in such an inclusionary way," Penn said. "You feel like there are reasonable people who have been on the other side of this conversation who are gonna listen to these kids."
Earlier this month, Penn was spotted on a romantic date with actress Amber Heard after attending a number of Oscars parties together.
"Amber Heard and Sean Penn looked like they were on a date," a source told Page Six after the two were spotted at the Tower Bar at Sunset Tower Hotel. "They shared a bottle of red wine and were flirty and intimate with each other, at times in deep conversation and at times laughing.