The 62-year-old star feels that some comics are so staunchly against the US President that they have neglected their main job of making audiences laugh.
O'Brien told the Oxford Union: "I think some comics go the route of, 'I'm just going to say F Trump all the time', or that's their comedy. And I think, well, now a little bit you're being co-opted because you're so angry.
"You've been lulled. It's like a siren leading you into the rocks. You've been lulled into just saying, 'F Trump. F Trump. F Trump. Screw this guy.' And I think you've now put down your best weapon, which is being funny, and you've exchanged it for anger."
The former Late Night with Conan O'Brien host doesn't subscribe to the argument that the political climate in the US shouldn't amuse people.
He said: "And that person or any person like that would say, 'Well, things are too serious now. I don't need to be funny.'
"And I think, well, if you're a comedian, you always need to be funny. You just have to find a way. And you just have to find a way to channel that anger.
"Because good art will always be a great weapon, will always be a perfect weapon against power, but if you're just screaming and you're just angry, you've lost your best tool in the toolbox."
O'Brien believes Trump's unpredictable nature makes it impossible for comics to parody the US president.
He said: "With Trump, we have a similar situation in comedy, which is people saying, 'We've got a great Trump sketch for you. In this one, he's kind of talking crazy... and he tears down half the White House to build a giant ballroom, and he says it's going to be the new Mar-a-Lago.'
"Yeah, no, that happened yesterday."
However, O'Brien still believes that comics should speak out as he criticised the decision to suspend Jimmy Kimmel Live! last September following the host's comments about the assassination of conservative activist Charlie Kirk.
He wrote on social media at the time: "The suspension of @jimmykimmel and the promise to silence other Late Night hosts for criticising the administration should disturb everyone on the Right, Left, and Centre. It's wrong and anyone with a conscience knows it's wrong."
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