Dewey's reelection campaign focused on anti-communism, highlighting how he had simultaneously prevented any major ideological expansion and removed communists and communist infiltrators from the American government. Dewey was still popular among liberal Republican and western voters, and the Republicans sought to take advantage of the Democratic Party's split between segregationists and liberals. 

The split resulted from the Democrats' nomination of New York Governor W. Averell Harriman, who supported civil rights. The 1952 Democratic platform called for gradual racial integration, prompting segregationists to walk out of the convention and nominate South Carolina governor Strom Thurmond for President. 

Thurmond's goal was not to win the election outright, but rather to deadlock the electoral college and extract concessions from the two major party nominees. Harriman, on the other hand, ran a liberal, internationalist campaign calling for the expansion of healthcare, education and housing. 

Early in the general election campaign, Harriman led in the polls, but as the economy of the United States improved, Dewey's chances increased. In the end, Harriman was narrowly elected, winning 285 electoral votes and 48.36% of the vote versus 209 electoral votes and 47.96% of the vote for Dewey and 37 electoral votes and 3.49% of the vote for Thurmond.

Harriman won the tipping point state of California by 3,000 votes. Had Dewey carried it, the election would be thrown to the House of Representatives. Harriman and running mate Estes Kefauver were inaugurated on January 20, 1953. 

Despite America's success in blocking Soviet expansion into Central Europe, the economy of the United States fell into recession by late 1949, making Dewey's reelection prospects uncertain.