Mulaney appeared wearing dark glasses on the Late Night clip, which was posted to YouTube on November 24, and he made some odd comments.
At one point, he referred to Prince Harry as a "dumb ginger" and called Meghan Markle a "silly goose" in a staged "Royal Watch: News from the Real-Life 'Crown'" segment and joked that the Sussexes were annoyed by the coronavirus pandemic as it took attention away from their Megxit "stunt."
"That’s the definition of something you wait out, gangsta," he said in regards to Prince Harry stepping down as a senior royal and dropping his title.
"I am pretty sure father time is going to sort out the case of the very old bummer woman who had 30 months to live," Mulaney said before adding, "Ahh, too mean."
At one point, he took off the glasses to show his eyes and said, "You know it’s weird, right, that Meghan and Harry left?" after he touched on Princess Diana’s death. "You thought rolling with those dorks in church clothes would be fun? Had you been told it was non-stop laughs?"
"Just the fact that she wanted to leave the royal family because they were like 'be proper and sit still' … So don’t marry into the family with the most jive-ass boring people ever and then be like, 'Oh, shall we play Never Have I Ever?'" he added.
Mulaney then described himself as "simple and difficult." Meyers commented, "I love having you on here, but in the future, if you just want to talk things like this out, a phone call might be better … We will see what of this we can use, but it might be online only."
"The next 'Royal Watch' will be a little more focused … Thank you Seth, and as a student reporter once wrote of me, 'Thank you for the laughs, albeit virtual,'" Mulaney chimed in.
After watching the clip, several fans were concerned about the comedian. "If you’ve watched @sethmeyers lately you had to know something was up," one fan wrote on Twitter. "Three weeks ago I felt there was something seriously *off* with John Mulaney’s appearance on Seth Meyers," another echoed.
"He just seemed very off in this segment and I was very confused it was odd to watch and see him like that but it makes sense now, unfortunately," a third user added.
"I'm genuinely so sad right now. Hope he gets better soon!" a fan commented on the video after the news broke.
A source told Page Six that Mulaney was "out of his mind" on substances while on appearing on the show, but his representative declined to comment.
As OK! previously reported, friends and family of Mulaney have been rallying around him after he sought help. "It was a relief to his wife and family that he checked in. It was John’s decision. Plain and simple, John had too much downtime. He had too much time in his own head," a source said.