Crist, who was Florida's Republican governor between 2007 and 2011, made the announcement on social media Tuesday.
"Florida should be a place where hard work is rewarded, justice is equal, and opportunity is right in front of you," Crist said in his announcement. "That's a Florida for all -- and that's why I'm running for governor."
In 2010, Crist became Florida's first governor in 46 years not to run for re-election. Instead, he ran for one of the state's U.S. Senate seats, which he ultimately lost to Florida House Speaker Marco Rubio.
Two years after leaving office, Crist left the GOP and registered as a Democrat. In 2014, he lost a bid to regain his job as governor to Republican Rick Scott.
In his announcement Tuesday, Crist revisited his work as Florida's 44th governor and the four years he's now been in the U.S. House.
"We protected 27,000 acres at the Everglades," he said. "Saved the jobs of 20,000 teachers, cut property taxes for our seniors, lowered the cost of prescription drugs, expanded children's healthcare ... restored voting rights for 150,000 Floridians. And we pulled together to pull our state out of the Great Recession."
Crist criticized DeSantis, Florida's governor since 2018 and considered by some to be a rising star in the Republican Party.
"While COVID took the lives of 35,000 Floridians, DeSantis attacked doctors and scientists," Crist said. "DeSantis is stripping away your voting rights. He's against the $15 minimum wage. He doesn't believe in background checks for guns, doesn't believe in a woman's right to choose, doesn't listen, he doesn't care. And unless you can write him a campaign check, you don't exist."
Crist's bid comes a day after DeSantis traveled to St. Petersburg district Monday to announce the end to all COVID-19 restrictions statewide, saying the state's coronavirus emergency is over. DeSantis has repeatedly been criticized since the pandemic began for various moves that were viewed as inadequate or politically motivated.