The governor was in Chattanooga, Tennessee for private fundraisers for his campaign.
His spokesperson, Bryan Griffin, said the accident happened when Mr DeSantis was traveling to an event.
His team are also unharmed. No further details were given about the incident.
"This morning, the governor was in a car accident while traveling to an event in Chattanooga, Tennessee. He and his team are uninjured. We appreciate the prayers and well wishes of the nation for his continued protection while on the campaign trail," Mr Griffin's statement read.
Mr DeSantis, 44, is vying for the Republican nomination in the upcoming 2024 presidential election, where he is expected to challenge former US president Donald Trump.