"He's a big bully," she told Tapper during a "Politics on Tap" event at Politicon. "He treats people terribly, he's disloyal ... he lies constantly. It's recorded lies. ... He's also unstable."
CNN has reached out to the White House for comment on Handler's remarks.
Handler, who's a sharp critic of Trump and often tweets about him, has gotten into politics on her Netflix talk show, "Chelsea," now in its second year.
She told CNN in April
that comedy and seriousness do not have to be mutually exclusive -- which is fitting for her appearance at Politicon, a conference aimed at having the left and right sit down and talk about political issues.
"I've become a better person, and I'm more informed. I'm learning," she told Tapper. "I have the Trump family to thank for that."
Handler also said she prefers her Netflix show over traditional television.
"Netflix is amazing, they let me do whatever I want," she said. "We got to film it all, and it's kind of an edification for me."
And she said because of Trump's administration, she can't avoid getting into politics.
"I thought that after the election I wouldn't do politics ... but that didn't happen, so I had to adjust," she said.
Handler added she would like to see Democratic Sens. Al Franken, Kirsten Gillibrand or Kamala Harris run for president.
"It would be great if Al Franken ran," she said. "I'll take anyone. Anyone. Please."