Thursday's show featured the Democratic presidential nominee playing along with Galifianakis as he continually asked irreverent and sometimes offensive questions.
"As secretary, how many words per minute could you type? And how does President Obama like his coffee? Like himself? Weak?" the comedian asked Clinton.
"You know, Zach, those are really out of date questions. You need to get out more," she replied.
"What happens if you get pregnant? Are we going to be stuck with Tim Kaine for nine months? How does this work," The Hangover star said, moving onto the next question.
"I could send you some pamphlets that might help you understand," said Clinton.
The interview also included some shots at Clinton's opponent Donald Trump, with Galifianakis asking Clinton if she would move to Canada if he won the election. "I would stay in the United States," Clinton says. "I would try to prevent him from destroying the United States."
The episode then ended with Galifianakis taking one final jab at Clinton, saying, "We should stay in touch. What's the best way to reach you? Email?"
Clinton's appearance on Between Two Ferns comes after her recent sit-down with Jimmy Fallon on The Tonight Show in which she referred to Trump's relationship with Russian President Vladimir Putin as a "bromance."
Back in 2014, President Obama appeared on Between Two Ferns in order to get young people to sign up for health insurance under the Affordable Care Act.