"Ladies and gentlemen, make some noise for the richest man in the world," Chappelle announced, as he brought Musk onto the stage.
The initial mixed reaction from the audience quickly became negative as the sound of booing took over the arena.
"You weren't expecting this, were you?" Musk sarcastically asked Chappelle.
Chappelle responded with humor, joking that "It sounds like some of the people you fired are in the audience."
He made a few more jokes in an attempt to lighten the mood, before ending the show, telling the audience that there are better ways to express their protest to Musk than booing.
Despite the show being a cell phone-free event, footage capturing the incident has been circulating on social media.
"Apparently there are a lot of CNN fans in San Francisco," one user wrote in response to the booing.
In response to another user's disparaging remark about the Twitter CEO's popularity, Musk said that "Technically, it was 90% cheers & 10% boos (except during quiet periods), but, still, that’s a lot of boos, which is a first for me in real life (frequent on Twitter)."
YouTuber Tim Pool joked that perhaps the audience was simply saying "boo-urns," referencing an old Simpsons joke.
"I saw the video and it was actually 97.3% Cheering and only one guy sitting next to the guy filming playing a clip from the simpsons of people yelling boo at Mr. Burns," he wrote.
"It’s almost as if I’ve offended SF’s unhinged leftists … but nahhh," he added.
Musk's relationship with San Francisco has soured recently, particularly following an announcement that the city would be launching an investigation into Twitter over reports that some of their offices had been turned into sleeping quarters for tired employees.
"So city of SF attacks companies providing beds for tired employees instead of making sure kids are safe from fentanyl," a reference to a story of a 10-month-old child nearly dying from an accidental fentanyl overdose in a playground. "Where are your priorities [mayor of San Francisco] @LondonBreed!?"
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