Wallace was born on October 7, 1888 at a farm near Orient, Adair County, Iowa. He graduated from Iowa State College at Ames in 1910, where he was a brother in the Delta Tau Delta fraternity. His father was Henry Cantwell Wallace. He worked on the editorial staff of Wallace's Farmer in Des Moines, Iowa, from 1910 to 1924 and edited the publication from 1924 to 1929. He experimented with breeding high-yielding strains of corn (maize), and authored many publications on agriculture. In 1915 he devised the first corn-hog ratio charts indicating the probable course of markets. With an inheritance of a few thousand dollars that had been left to his wife, the former Ilo Browne, whom he married in 1914, Wallace founded Hi-Bred Corn, which later became Pioneer Hi-Bred, a major agriculture corporation, acquired in 1999 by the Dupont Corporation for approximately $10 billion.

Wallace was raised as a Presbyterian, but left that denomination early in life. He spent most of his early life exploring other religious faiths and traditions. For many years, he had been closely associated with famous Russian artist and writer Nicholas Roerich. According to Arthur Schlesinger, Jr., "Wallace's search for inner light took him to strange prophets.... It was in this search that he encountered Nicholas Roerich, a Russian emigre, painter, theosophist. Wallace did Roerich a number of favors, including sending him on an expedition to Central Asia presumably to collect drought-resistant grasses. In due course, H.A. [Wallace] became disillusioned with Roerich and turned almost viciously against him." Wallace eventually settled on Episcopalianism.

In 1933, President Franklin D. Roosevelt appointed Wallace United States Secretary of Agriculture in his Cabinet, a post his father, Henry Cantwell Wallace, had occupied from 1921 to 1924. Wallace had been a liberal Republican, but he supported Roosevelt's New Deal and soon switched to the Democratic Party. Wallace served as Secretary of Agriculture until September 1940, when he resigned, having been nominated for Vice President as Roosevelt's running mate in the 1940 presidential election. During his tenure as U.S. Secretary of Agriculture he had to order a very unpopular strategy of slaughtering pigs and plowing up cotton fields in rural America to drive the price of these commodities back up in order to improve American farmers' financial situation. He also advocated the ever-normal granary concept.

Wallace was elected in November 1940 as Vice President on the Democratic Party ticket with President Franklin D. Roosevelt. His inauguration took place on January 20, 1941, for the term ending January 20, 1945.

Roosevelt named Wallace chairman of the Board of Economic Warfare (BEW) and of the Supply Priorities and Allocations Board (SPAB) in 1941. Both positions became important with the U.S. entry into World War II. As he began to flex his newfound political muscle in his position with SPAB, Wallace came up against the conservative wing of the Democratic party in the form of Jesse H. Jones, Secretary of Commerce, as the two differed on how to handle wartime supplies.

On May 8, 1942, Wallace delivered his most famous speech, which became known by the phrase "Century of the Common Man" to the Free World Association in New York City. This speech, grounded in Christian references, laid out a positive vision for the war beyond the simple defeat of the Nazis. The speech, and the book of the same name which appeared the following year, proved quite popular, but it earned him enemies among the Democratic leadership, among important allied leaders like Winston Churchill, and among business leaders and conservatives.

Wallace spoke out during race riots in Detroit in 1943, declaring that the nation could not "fight to crush Nazi brutality abroad and condone race riots at home."

In 1943, Wallace made a goodwill tour of Latin America, shoring up support among important allies. His trip proved a success, and helped persuade twelve countries to declare war on Germany. Regarding trade relationships with Latin America, he convinced the BEW to add "labor clauses" to contracts with Latin American producers. These clauses required producers to pay fair wages and provide safe working conditions for their employees and committed the United States to paying for up to half of the required improvements. This met opposition from the U.S. Department of Commerce.

Wallace believed that both the American and the Russian revolution were part of "the march to freedom of the past 150 years." After having met Molotov, he arranged a trip to the "Wild East" of Russia. On May 23, 1944, he started a 25-day journey accompanied by Owen Lattimore. Coming from Alaska, they landed at Magadan where they were received by Sergei Goglidze and Dalstroi director Ivan Nikishov, both NKVD generals. The NKVD presented a fully sanitized version of the slave labor camps in Magadan and Kolyma to their American guests, convinced them that all the work was done by volunteers, charmed them with entertainment, and left their guests impressed with the "development" of Siberia and the spirit of the "volunteers". Lattimore's film of the visit tells that " a village .. in Siberia is a forum for open discussion like a town meeting in New England." The trip then continued to China.

After Wallace feuded publicly with Jesse Jones and other high officials, Roosevelt stripped him of his war agency responsibilities and entertained the idea of replacing him on the presidential ticket. The Democratic Party, with concern being expressed privately about Roosevelt being able to make it through another term, chose Harry S. Truman as Roosevelt's running mate at the 1944 Democratic convention, after New Deal partisans failed to promote William O. Douglas. Wallace was succeeded as Vice President on January 20, 1945, by Truman. On April 12, 1945, Vice President Truman succeeded to the Presidency when President Franklin D. Roosevelt died. Henry A. Wallace had missed being the 33rd President of the United States by just 82 days.