Uncle Henry's son, and Henry A. Wallace's father, was Henry Cantwell Wallace, a farmer, newspaper Editor, university professor and author who would serve as the Secretary of Agriculture in the Republican administrations of Warren G. Harding and Calvin Coolidge. Henry Agard was born on October 7, 1888, at a farm near the village of Orient, Iowa, in Adair County, but the family later moved to Des Moines. Wallace's mother, née May Brodhead, was deeply religious. She had been to college and was trained in music and art.

Wallace attended Iowa State College in Ames, Iowa, graduating in 1910 with a bachelor's degree in animal husbandry. During his time at Iowa State, Wallace was a member of the Delta Tau Delta fraternity. He worked on the editorial staff of the family-owned paper Wallaces' Farmer in Des Moines from 1910 to 1924, and took the role of chief Editor from 1924 to 1929. Wallace experimented with breeding high-yielding Hybrid corn, and wrote a number of publications on agriculture. In 1915, he devised the first corn-hog ratio charts indicating the probable course of markets. Wallace was also a practicing statistician, writing an influential article with pioneering statistician George W. Snedecor of Iowa State University on computational methods for correlations and regressions and publishing sophisticated statistical studies in the pages of Wallaces’ Farmer. Snedecor invited Wallace to teach a graduate course on least squares. It was Wallace, more than any other individual, who introduced econometrics (a form of statistical analysis used by economists) to the field of agriculture.

Roerich, who styled himself a guru (or teacher), designed the sets and co-wrote the scenario for Igor Stravinsky's 1913 avant garde ballet The Rite of Spring. During the 1920s, Roerich traveled to Tibet, considered by theosophists a repository of ancient wisdom, and in 1930 he published a book, Shambhala: In Search of the New Era, a collection of traditional legends of Tibetan Buddhism: (1930). Roerich later gained international Celebrity through his lobbying for the protection of the world's cultural, scientific, and artistic monuments from the ravages of war, a cause Wallace, along with such luminaries as Albert Einstein, George Bernard Shaw, and H.G. Wells adopted. Both Wallace and Roosevelt successfully lobbied Congress to support Roerich's Banner and Pact of Peace campaign, and in 1935 delegates from 22 Latin American countries met in Washington, D.C., to sign the pact. Roosevelt, who perhaps came by an interest in Asian religions through his mother Sara, also exchanged letters with Helena [Ivanova] Roerich.

In 1914, Wallace married Ilo Browne, and in 1926, with the help of a small inheritance that had been left to her, he founded the Hi-Bred Corn Company, which made him a wealthy man. The company later became Pioneer Hi-Bred, a major agriculture corporation. It was acquired in 1999 by the DuPont Corporation for approximately $10 billion.

The son of Secretary of Agriculture Henry Cantwell Wallace, Henry A. Wallace was born in Adair County, Iowa. After earning a degree in animal husbandry from Iowa State University, Wallace worked as a farmer and newspaper Editor. He founded the Hi-Bred Corn Company, which experienced immense success and made Wallace wealthy. Wallace also helped introduce the use of statistics and econometrics in agriculture. Starting in the 1920s, he explored various religions, becoming interested in Theosophy and befriending figures such as George william Russell and Nicholas Roerich.

Wallace was raised as a Presbyterian. In college, however, he became increasingly dissatisfied with organized religion after reading william James' The Varieties of Religious Experience (1902). Around 1919 he stopped attending the Presbyterian church and spent the next ten years exploring other religious faiths and traditions, including spiritualism and esoteric religion. He later said, "I know I am often called a mystic, and in the years following my leaving the United Presbyterian Church I was probably a practical mystic ... I'd say I was a mystic in the sense that George Washington Carver was – who believed God was in everything and therefore, if you went to God, you could find the answers." Wallace joined the Theosophical Society on June 6, 1925, and that same year helped organize a Des Moines parish of the Liberal Catholic Church, a denomination with ties to Theosophy, but which had no ties to the Roman Catholic Church. He resigned from the Theosophical Society on or before November 23, 1935, and in 1939 formally joined the Episcopal Church.

During the 1930s Wallace also engaged in an exchange of notes with Russian émigré, Artist, mystic, and peace Activist Nicholas Roerich, his wife Helena Ivanova, and some of their associates at the Roerich Museum in New York. Both Nicholas and, especially, Helena, had developed their own brand of Theosophy that they called Living Ethics or Agni Yoga, which emphasized a Common thread running through all religions. Nicholas Roerich had been nominated for the Nobel Peace Prize and invited to Herbert Hoover's White House. Wallace had met Roerich in 1929, and Franklin and Eleanor Roosevelt were also acquainted with him.

In 1933, the Roosevelt administration, which had just formally recognized the Soviet Union, sent Nicholas Roerich and his Harvard-educated son George, who had studied Asian languages and later became a noted scholar of Tibet, on a horticultural expedition to Central Asia on behalf of Wallace's Department of Agriculture. Arthur M. Schlesinger, Jr., who was hostile to Wallace, writes that "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 biographers John C. Culver and John Hyde, however, write that it is unclear with whom the idea for the Roerich expedition originated, since in cabinet meetings Wallace had opposed Roosevelt's granting of recognition to the Soviet government because of its hostility to organized religion and his fear it would dump grain on the United States. However, once in Asia, Roerich upset the diplomatic world and the US agricultural experts who accompanied him by neglecting botany and, instead, searching for and possibly trying to bring about a revival of the legendary Shambhalla, variously located in Tibet, Bhutan, Nepal, or Manchuria. These areas were partly under the jurisdiction of the British and Japanese empires, which did not look kindly on movements for national self-determination and believed Roerich to be a Russian spy and/or anti-imperialist agitator. After Wallace recalled him, the U.S. government aggressively pursued Roerich for tax evasion, and the Artist (the holder of a French passport) took up residence in India, where gurus were not considered so unusual.

Roosevelt also introduced Wallace to The Glory Road (1935), a novel by popular Broadway Playwright Arthur Hopkins. Not a religious book, The Glory Road was a historical-political allegory inspired by the economic devastation wrought by the Great Depression. On its dust jacket The Glory Road is said to describe "the experience of the human race as it has tried to follow the road of truth while at the same time building up for itself a structure of civilization that will yield material wealth". Culver and Hyde identify this book as the source of the pen-names Wallace later adopted in some of his correspondence – perhaps including the so-called "Guru letters". For Example, in a letter to FDR, Wallace says, "You can be 'the flaming one'." Arthur Schlesinger, Jr. describes Wallace's references to figures in The Glory Road (such as "the fervent one" and so on), as "rash" and "cabalistic", bespeaking what Schlesinger calls "moods of rapture." However, Wallace's use of the term in addressing Roosevelt is likely an in-joke, since in The Glory Road there is no "flaming one", but rather a "flameless one', "elected as his people's executive", supported by Bankers and corrupt Leaders, who urges the electorate to "buy, buy, buy" as a way out of economic collapse.

The ticket found favor with the electorate, however. In November 1940, Roosevelt was handily re-elected for a third term – the Electoral College vote was 449 to 82.

Roosevelt named Wallace chairman of the Board of Economic Warfare (BEW) and of the Supply Priorities and Allocation 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 what became his most famous speech, to the Free World Association in New York City. The speech, delivered during the darkest days of the war, was formally titled "The Price of Free World Victory" but came to be identified by its phrase "the century of the Common man". This was Wallace's answer to Republican publisher Henry Luce's call for an "American Century" after the war. For Wallace the war was a conflict between the slave states and the free world.

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 Department of Commerce.

After meeting Vyacheslav Molotov, Wallace arranged a trip to the "Wild East" of Soviet Union. 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 Sergo Goglidze and Dalstroi Director Ivan Nikishov, both NKVD generals. The NKVD presented a fully sanitized version of the labor camps in Magadan and Kolyma to their American guests, claiming that all the work was done by volunteers. The delegation was provided with entertainment, and by some accounts left 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." This visit took place while the United States and the Soviet Union were allies; American propaganda regularly portrayed the Soviet Union in a positive light. The trip continued through Mongolia and then to China.

On March 1, 1945, Wallace was confirmed by a vote of 56-31. Five Democrats, four of whom were Southern Democrats, voted against Wallace's confirmation.

The outspoken Wallace continued to be controversial, exasperating conservatives and moderates, and even, at times, his allies. His conservative opponents were infuriated when Wallace objected that a militaristic stance toward the Soviet Union was likely to be counterproductive, while his left-leaning audiences booed when he criticized the Soviets. In a speech delivered on April 12, 1946, Wallace distanced himself from the United States' former wartime allies, stating that "aside from our Common language and Common literary tradition, we have no more in Common with Imperialistic England than with Communist Russia". Historian Tony Judt (who calls Wallace "notoriously 'soft' on Communism"), notes that at the time such "distaste for American involvement with Britain and Europe was widely shared across the political spectrum." Most Americans, he writes, wanted neither European alliances nor expected American troops to be stationed overseas. For a time, Truman himself appeared undecided. By September 1946, however, Truman had fired Wallace, the last of FDR's appointees still in office, having dismissed all of the others in the first 12 months of his presidency. Wallace is the last former vice President to serve in a president's cabinet.

Following his term as Secretary of Commerce, Wallace became the Editor of The New Republic magazine, which he used as a platform to oppose Truman's foreign policies. On the declaration of the Truman Doctrine in 1947, he predicted it would mark the beginning of "a century of fear".

Wallace left his editorship position in 1948 to make an unsuccessful run as the Progressive Party's presidential candidate in the 1948 presidential election. With Idaho Democratic Senator Glen H. Taylor as his vice presidential running mate, his platform advocated universal government health insurance, an end to the nascent Cold War, full voting rights for black Americans, and an end to segregation. His campaign included African American candidates campaigning alongside white candidates in the segregated South and he also refused to appear before segregated audiences or to eat or stay in segregated establishments.

In 1950 during the McCarthy era, when North Korea invaded South Korea, Wallace broke with the Progressives and backed the U.S.-led effort in the Korean War. Despite this, according to Wallace's diary, after his 1951 Senate Internal Security Subcommittee testimony, opinion polls showed that he was only beaten by gangster Lucky Luciano as the "least approved man in America". Previously, after hearing from Gulag survivor and friend Vladimir Petrov about the true nature of the 1944 Vice Presidential visit to Magadan, Wallace had publicly apologized for having allowed himself to be fooled by the Soviets. In 1952 Wallace published Where I Was Wrong, in which he explained that his seemingly-trusting stance toward the Soviet Union and Joseph Stalin stemmed from inadequate information about Stalin's crimes, and that he now considered himself an anti-Communist.

He wrote various letters to "people who he thought had traduced [maligned] him" and advocated the re-election of President Dwight D. Eisenhower in 1956. In 1961, President-elect John F. Kennedy invited Wallace to his inauguration ceremony, even though he had supported Kennedy's opponent Richard Nixon. (Like Wallace, Nixon had been Vice President before becoming a presidential candidate.) A touched Wallace wrote to Kennedy: "At no time in our history have so many tens of millions of people been so completely enthusiastic about an Inaugural Address as about yours."

Wallace first experienced the onsets of amyotrophic lateral sclerosis in 1964. He died in Danbury, Connecticut, on November 18, 1965. His remains were cremated and the ashes interred in Glendale Cemetery in Des Moines, Iowa.

As of 2018, he remains the last Democratic vice President who never served in the United States Senate and indeed the last vice President of any party who had not previously held any elected office.