His show debut also involved him flying on a broomstick singing “there’s no place like Rome”, in a nod to the new Wicked movie, for a sketch where Gladiator II had been turned into a musical.
Recent monologues on the programme have come from stars including comedian John Mulaney and singers Charli XCX and Ariana Grande.
The Normal People star, 28, said: “I do take great pride in being Irish.
“The Irish people have been through a lot, you know, centuries of British occupation, the great famine, mass emigration, that U2 album that automatically got downloaded on everyone’s phones.
“So before we start the show, I just want to clear up some ugly stereotypes about the Irish.
“For example, there’s a nasty rumour that Irish people have sex with our cousins, right? That’s offensive and ridiculous. We have sex with our second cousins.
“People also think the Irish hate British people. That’s not true. We just don’t consider them people.
“Sometimes people ask me if I think Notre Dame’s mascot, the Fighting Irish, is offensive. Not at all.
“We do the same thing with the Americans.
“In fact, my high school’s mascot was the fighting fat asses.”
Then, in reference to commentary online about the shorts Mescal has been pictured wearing, he said: “A lot of people ask if we wear kilts, no, that’s the Scottish.
“Traditionally, the Irish wear short shorts.”
The 28-year-old actor, portrays a grown-up Lucius Verus in Sir Ridley Scott’s new historical epic, Gladiator II, which premiered last month.
Speaking to US outlet Variety on the red carpet of the film’s Los Angeles premiere, Mescal reflected on his experience of meeting Britain’s King Charles.
He said: “How wild is it? It’s definitely not something that I thought was in the bingo cards.
“I’m Irish, so it’s not on the list of priorities. But it’s an amazing thing for Ridley because I know how important that is for him.
“So to see his film celebrated in that context was pretty special.”
Recalling his encounter with Charles, Mescal admitted he found it hard to hear what was being said amid the excitement of the premiere so he was “nodding along and smiling”.
The film’s world premiere was in London, and it marked the first premiere Charles attended as king.
He also met with Mescal’s co-stars including Oscar-winner Denzel Washington and Narcos star Pedro Pascal.
Gladiator II is set years after the Oscar-winning 2000 film, which starred Russell Crowe as Roman general Maximus Decimus Meridius.
The second film tells the story of Lucius, who originally appeared in the film as a child.
Lucius escaped capture after the fall of Commodus, played by Joaquin Phoenix in the original movie, and joined the fight against the Roman Empire’s expansion.
In the fight to defend his wife, Lucius is captured and placed into slavery by the forces of Marcus Acacius (Pascal) and subsequently becomes a gladiator after being bought by Macrinus (Washington), and seeks revenge.