William Lockhart Clayton, cotton merchant, was born on a farm near Tupelo, Mississippi, on February 7, 1880, to James Munroe and Martha Fletcher (Burdine) Clayton. He attended seven grades of public school in Tupelo and Jackson, Tennessee, where the family moved when he was six years old. Proficient in shorthand, he went to St. Louis in 1895 as personal secretary to an official of the American Cotton Company. From 1896 to 1904 he worked in the New York office of the American Cotton Company, where he rose to the position of assistant general manager. In 1904 Clayton formed a partnership to buy and sell cotton with two members of a Jackson, Tennessee, family prominent in banking-Frank E. and Monroe D. Anderson, the former Clayton's brother-in-law. A younger brother, Benjamin Clayton, joined the firm in 1905. Anderson, Clayton and Company first opened its offices in Oklahoma City and experienced immediate success. In 1916 the firm moved its headquarters to Houston, where Clayton, as the partner most expert in foreign sales, led other cotton exporters in providing warehouse facilities, insurance, credit, and other services that European firms had formerly rendered. In 1920 the company reorganized as an unincorporated Texas joint-stock association. Later in the 1920s Clayton led the fight that forced the New York Stock Exchange to accept southern delivery on futures contracts, thus removing an impediment to the natural operation of the futures market.
When high tariffs and federal farm-price supports threatened to drive American cotton out of the world market in the late 1920s and early 1930s, Clayton's firm responded by establishing cotton-buying offices in Latin America and Africa in order to supply its foreign sales agencies with cotton at competitive rates. At the same time that Clayton was expanding his business abroad, he fought the farm policies of the New Deal. He opposed government supports of the agricultural market. Instead, he believed that if subsidies were necessary they should go straight to the farmer. Clayton joined the American Liberty League in 1934 but left the organization the following year, when it failed to accept his recommendations for public relations in Texas. In 1936 he renounced his earlier opposition to Roosevelt because of Secretary of State Cordell Hull's work for a reciprocal trade agreement, a cause Clayton had advocated for many years. Meanwhile, Anderson, Clayton and Company increased investments in cotton gins, vegetable-oil mills, feed factories, experimental seed farms, and other enterprises related to processing cotton and similar commodities. From the beginning such investments had made the firm unique among cotton-merchandising organizations. Frank Anderson died in 1924, and Benjamin Clayton withdrew from the firm in 1929. The two remaining partners formed Anderson, Clayton and Company (Delaware) in 1930 and issued preferred stock. In 1940 Clayton retired from active management in the firm, but through several trusts he maintained control of the company until his death.
During World War I he served on the Committee of Cotton Distribution of the War Industries Board. In 1940 he was called to Washington to serve as deputy to the coordinator of inter-American affairs. For the next four years he held a variety of high-level positions with the Export-Import Bank, the Department of Commerce, and wartime agencies. From December 1944 until October 1947 he was assistant and then undersecretary of state for economic affairs, in which capacity he became a principal architect of the European Recovery Program, known commonly as the Marshall Plan. After his return to Houston in late 1947, he remained an occasional participant and frequent contributor to international conferences on world trade, the European Common Market, and related matters.
He contributed personally and through the Clayton Fund to a variety of religious, charitable, and educational institutions, most notably to Johns Hopkins University (of which he was a trustee from 1949 to 1966), Tufts University, the University of Texas, Susan V. Clayton Homes (a low-cost housing project in Houston), and the Methodist Church. Clayton married Susan Vaughan of Clinton, Kentucky, on August 14, 1902. They had a son who died in infancy and four daughters who survived them. Clayton died after a brief illness on February 8, 1966, and was buried in Glenwood Cemetery, Houston.