Landon was born in 1887 in West Middlesex, Pennsylvania, the son of Anne (Mossman) and John Manuel Landon. Landon grew up in Marietta, Ohio. He moved with his family to Kansas at age 17 and graduated from the University of Kansas in 1908. Alfred first pursued a career in banking, but in 1912 he became an independent petroleum Producer in Independence, Kansas. During World War I, Landon served in the Army as a first lieutenant in chemical warfare.

By 1929, the oil industry had made Alf a millionaire, and he was instrumental in the establishment of the Kansas-Oklahoma division of the United States Oil and Gas Association, then known as the Mid-Continent Oil and Gas Association, a petroleum lobbying organization.

The Republicans' defeats in 1932 and 1936 plunged their party into a period of bitter intraparty strife. Landon played an important role in ending this internal bickering in 1938, in helping to prepare a new group of Leaders for the presidential campaign of 1940, and in trying to bring about a compromise between the isolationist and internationalist viewpoints in foreign policy. Landon declined a position in Franklin Roosevelt's Cabinet because he made his acceptance contingent upon the President's renunciation of a third term.

Republican primary for Governor of Kansas, 1934

The 1936 presidential election was extraordinarily lopsided. Although Landon gained nearly seventeen million votes and obtained the endorsement of track star Jesse Owens, he lost the popular vote by more than 10 million votes. He lost his home state Kansas and carried only Maine and Vermont for a total of eight electoral votes to Roosevelt’s 523. In fact on the same day Kansas rejected Landon for the presidency the state also elected Democrat Walter A. Huxman as his successor as governor. FDR’s win was the most crushing electoral victory since the 1820 election. The overwhelming Roosevelt victory prompted Democratic Party boss James Farley to joke, “As Maine goes, so goes Vermont”.

After war broke out in Europe in 1939 Landon fought against isolationists such as America First who supported the Neutrality Act; he feared it would mislead Nazi Germany into thinking the United States was unwilling to fight. In 1941, however, he joined isolationists in arguing against lend-lease, although he did urge that Britain be given $5 billion outright instead. After the war, he backed the Marshall Plan, while opposing high domestic spending. After the communist revolution in China, he was one of the first to advocate recognition of Mao Zedong's communist government, and its admission to the United Nations, when this was still a very unpopular position among the leadership and followers of both major parties.

In 1961, Landon urged the U.S. to join the European Common Market. In November 1962, when he was asked to describe his political philosophy, Landon said: "I would say practical progressive, which means that the Republican party or any political party has got to recognize the problems of a growing and complex industrial civilization. And I don't think the Republican party is really wide awake to that." Later in the 1960s, Landon backed President Lyndon Johnson on Medicare and other Great Society programs.

On December 13, 1966, Landon gave the first "Landon Lecture" at Kansas State University in Manhattan, Kansas. Landon's lecture, titled "New Challenges in International Relations" was the first in a series of public issues lectures that continues to this day and has featured numerous world Leaders and political figures, including seven U.S. Presidents (Richard Nixon, Gerald Ford, Jimmy Carter, Ronald Reagan, George H. W. Bush, Bill Clinton and George W. Bush).

Landon addressed the Republican National Convention in 1976 in Kansas City.

Landon died in Topeka on October 12, 1987 at 5:25 p.m., thirty-three days after celebrating his hundredth birthday, and is interred at Mount Hope Cemetery in Topeka. He is the only presidential candidate from a major party to live to at least one hundred years of age (Strom Thurmond reached an age that was a few months older than Landon's but he was a minor party presidential candidate).

Landon respected and admired Roosevelt and accepted much of the New Deal but objected that it was hostile to Business and involved too much waste and inefficiency. Late in the campaign, Landon accused Roosevelt of corruption – that is, of acquiring so much power that he was subverting the Constitution. Landon said:

Landon’s daughter, Nancy Landon Kassebaum, was a United States Senator from Kansas. Elected to the U.S. Senate in 1978, she was re-elected in 1984 and 1990. Her second husband was her former Senate colleague Howard Henry Baker, Jr., of Tennessee (1925–2014).