Sparkman served as Adlai Stevenson's running mate in the 1952 presidential election, but they were defeated by the Republican ticket of Dwight D. Eisenhower and Richard Nixon.

Known as a defender of segregation during the Civil Rights era, Sparkman voted regularly against civil rights legislation and condemned the "judicial usurpation" of the U.S. Supreme Court decision of Brown v. Board of Education, Sparkman signed the 1956 Southern Manifesto, which pledged opposition to racial integration and promised to use "all lawful means" to fight the ruling that put court power behind the integration of public institutions.

Sparkman took a pro-British foreign policy stance, advocating the United States should assist Great Britain in the war against the Nazis.

According to his citation from the Alabama Academy of Honor Archived 2020-02-11 at the Wayback Machine, into which Sparkman was inducted in 1969, as a Member of the House of Representatives, "[Sparkman] gained renown for his sponsorship of such programs as the farm-tenant purchase program, rehabilitation loans for small farmers, and lower interest rates for farm loans.

In 1949, Sparkman was instrumental in convincing the United States Department of the Army to transfer the missile development activities from Fort Bliss, Texas, to Redstone Arsenal.

This brought Wernher von Braun and the German Operation Paperclip scientists and engineers to Huntsville, forming the foundation to what eventually became the NASA Marshall Space Flight Center.

[4] In January 1951, Sparkman stated that he believed the Truman administration housing defense program could increase inflationary pressures, a view that aligned with Republican senators Irving Ives and Andrew Frank Schoeppel, but furthered that the plan was essential and should be undertaken regardless of inflation concerns.

After the election, Sparkman in an interview expressed approval that American small businessmen were giving large firms competition for foreign aid contracts.

"[23] In January 1955, the University of Alabama News Bureau released remarks of Sparkman he had made during an interview following the 1954 midterm elections.

[24] On January 21, 1955, Sparkman introduced a bill authorizing $50 million in appropriation each quarter of the year for G.I.s to see a reduction dependent on the sales of home mortgages to private lenders of properties owned by the Veterans Administration.

[25] On February 2, 1955, during an interview, Sparkman said the US would have to weigh giving Nationalist islands to Red China if the United Nations succeeded in imposing a cease-fire in Formosa.

[26] In February 1955, Sparkman criticized the farming policies of the Eisenhower administration, charging them with having hurt the financial situations of American farmers the most since before the beginning of World War II and that the plight of farmers would continue so long as legislation affecting controls on crop acreage and the flexible price support system was enacted.

"[29] In 1956, Sparkman was one of 82 representatives and 19 senators who signed the Southern Manifesto opposing the 1954 U.S. Supreme Court decision Brown v. Board of Education and racial integration.

[32] During the September 4, 1964 signing of the Housing Act of 1964 by President Lyndon B. Johnson, the latter expressed his "very special congratulations this morning to both Senator Sparkman and Congressman Rains of Alabama.

[35] On July 9, 1964, President Johnson signed the Urban Mass Transportation Act of 1964 into law, observing Sparkman was one of the members of Congress who helped in securing the legislation's passage.

In 1966, Sparkman defeated another Republican, John Grenier, the former state GOP chairman and an attorney from Birmingham, who polled 39 percent of the vote.

[39] In his last Senate race in 1972, Sparkman easily defeated President Nixon's former postmaster general, the Republican businessman Winton M. Blount of Montgomery, originally from Union Springs.

Blount, running without a specific endorsement from President Nixon, first had to dispatch intraparty Republican rivals Martin and Alabama State Representative Bert Nettles.

On November 16, 1985, Sparkman died of a heart attack at Big Springs Manor Nursing Home in Huntsville, Alabama, a month before his 86th birthday.