In 2004, during his second year at Harvard Law, DeSantis was commissioned as an officer in the U.S. Navy and assigned to the Navy Judge Advocate General's Corps (JAG). He completed Naval Justice School in 2005. Later that year, he reported to the JAG Trial Service Office Command South East at Naval Station Mayport, Florida, as a prosecutor. He was promoted from lieutenant, junior grade to lieutenant in 2006.

In the spring of 2006, DeSantis arrived at Joint Task Force Guantanamo (JTF-GTMO), working with detainees at the Guantanamo Bay detention camp. The publicly released records of his service in the Navy were redacted, with the Navy citing a personal-privacy exception to the Freedom of Information Act. Mansur Ahmad Saad al-Dayfi, who was held at Guantanamo, alleged in 2022 that DeSantis oversaw force-feeding detainees and DeSantis acknowledged that he advised the commander of the base about the use of force feeding.

In 2007, DeSantis reported to the Naval Special Warfare Command Group in Coronado, California, where he was assigned as a legal adviser to SEAL Team One; he deployed to Iraq in the fall of 2007 as part of the troop surge. He served as legal adviser to Dane Thorleifson, the SEAL Commander of the Special Operations Task Force-West in Fallujah.

DeSantis returned to the U.S. in April 2008, reassigned to the Naval Region Southeast Legal Service. He was appointed to serve as a special assistant U.S. attorney at the U.S. Attorney's Office in the Middle District of Florida. DeSantis was assigned as a trial defense counsel until his honorable discharge from active duty in February 2010. He concurrently accepted a reserve commission as a lieutenant in the Judge Advocate General's Corps of the U.S. Navy Reserve.

During his military career, DeSantis was awarded the Bronze Star Medal, the Navy and Marine Corps Commendation Medal, the Global War on Terrorism Service Medal, and the Iraq Campaign Medal. His Navy Reserve service ended in February 2019, a month after his gubernatorial inauguration, with the rank of lieutenant commander.
With two law-school friends, DeSantis founded an LSAT test-prep company, LSAT Freedom, that one of the other co-founders billed as "the only LSAT prep courses designed exclusively by Harvard Law School graduates". DeSantis also worked as a litigator at the Miami-based law firm Holland & Knight before running for Congress in 2012.

In 2012, DeSantis ran for the U.S. House of Representatives from Florida's 6th congressional district. During his campaign, he aligned himself with the conservative Tea Party movement. His campaign was financially supported by the Koch Brothers' organizations FreedomWorks and Club for Growth. U.S. senator Mike Lee and former United Nations ambassador John Bolton helped DeSantis campaign and raise money. In August, DeSantis defeated six candidates in the Republican primary and then defeated Democratic nominee Heather Beaven in the November general election. He was reelected in 2014 and 2016.

In May 2015, DeSantis announced his candidacy for the 2016 United States Senate election in Florida. He ran for the seat held by Marco Rubio, who initially did not file to run for reelection due to his 2016 presidential campaign. DeSantis was endorsed by the Koch Brothers' fiscally conservative Club for Growth, which had previously supported his U.S. House campaign. When Rubio ended his presidential bid and ran for reelection to the Senate, DeSantis withdrew from the Senate race, instead running for reelection to the House.
DeSantis signed a 2013 "No Climate Tax Pledge" against any tax hikes to fight global warming. He voted in favor of H.R. 45, which would have repealed the Affordable Care Act in 2013. DeSantis introduced a bill in 2014 that would have required the Justice Department to report to Congress whenever any federal agency refrained from enforcing laws. In 2015, DeSantis was a founding member of the Freedom Caucus, a group of congressional conservatives and libertarians.

DeSantis opposes gun control and received repeated "A" ratings from the NRA Political Victory Fund. He has said, "Very rarely do firearms restrictions affect criminals. They really only affect law-abiding citizens."

DeSantis was a critic of Obama's immigration policies, including deferred action legislation (DACA and DAPA), accusing Obama of failing to enforce immigration laws. In 2015 he co-sponsored Kate's Law, which would have increased penalties for aliens who unlawfully reenter the U.S. after being removed. DeSantis encouraged Florida sheriffs to cooperate with the federal government on immigration-related issues.

In 2016, DeSantis introduced the Higher Education Reform and Opportunity Act, which would have allowed states to create their own accreditation systems. He said this legislation would also give students "access to federal loan money to put towards non-traditional educational opportunities, such as online learning courses, vocational schools, and apprenticeships in skilled trades".

In 2016, DeSantis received a "0" rating from the

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DeSantis was elected governor of Florida in 2018 and reelected in 2022. He is not eligible to run for a third term in 2026.
On January 5, 2018, DeSantis filed to run for the office of governor to replace term-limited Republican incumbent Rick Scott. President Trump had said the previous month that he would support DeSantis should he run for governor. During the Republican primary, DeSantis emphasized his support for Trump by running an ad in which DeSantis taught his children how to "build the wall" and say "Make America Great Again". Asked whether he could name an issue on which he disagreed with Trump, DeSantis declined. On August 28, 2018, DeSantis won the Republican primary, defeating his main opponent, Adam Putnam.

DeSantis's gubernatorial platform included support for legislation that would allow people with concealed weapons permits to carry firearms openly. He also supported a law mandating the use of E-Verify by businesses and a state-level ban on sanctuary city protections for undocumented immigrants. DeSantis promised to stop the spread of polluted water from Lake Okeechobee. He expressed support for a state constitutional amendment to require a supermajority vote for any tax increases. DeSantis opposed allowing able-bodied, childless adults to receive Medicaid. He said he would implement a medical cannabis program, while opposing the legalization of recreational cannabis.

The day after his primary win, in a televised Fox News interview, DeSantis said, "The last thing we need to do is to monkey this up by trying to embrace a socialist agenda with huge tax increases and bankrupting the state." His use of the word "monkey" received widespread media attention, and was interpreted by some, including Florida Democratic Party chair Terrie Rizzo, as a racist dog whistle alluding to the Democratic gubernatorial nominee, Andrew Gillum, who is African-American. DeSantis denied the racism charge. Dexter Filkins, writing in The New Yorker in 2022, called it a "disastrous gaffe," and quoted an unnamed ally of DeSantis lamenting that afterward, "We were handling Gillum with kid gloves. We can't hit the guy, because we're trying to defend the fact that we're not racist."

The general election was "widely seen as a toss-up." Some sheriffs endorsed DeSantis, while other sheriffs backed Gillum. DeSantis was endorsed by the Florida Police Chiefs Association. On September 5, he announced state representative Jeanette Núñez as his running mate. He resigned his House seat on September 10 to focus on his gubernatorial campaign. The same month, he canceled a planned interview with the Tampa Bay Times to have additional time to put toge…

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