By 1921 he had been elected president of the UMWA. Lewis quickly asserted himself as a dominant figure in what was then the largest and most influential trade union in the country.
Lewis was considered by some a despotic leader of the Mine Workers: he expelled his political rivals within the UMWA, such as John Brophy and Adolph Germer. Communists in District 26 (Nova Scotia), including Canadian labor legend JB McLachlan, were banned from running for the union executive after a strike in 1923. McLachlan described him as "a traitor to the working class". Lewis nonetheless commanded great loyalty from many of his followers, even those he had exiled in the past.
A powerful speaker and strategist, Lewis used the nation's dependence on coal to increase the wages and improve the safety of miners, even during several severe recessions. He masterminded a five-month strike, ensuring that the increase in wages gained during World War I would not be lost.
Lewis challenged Samuel Gompers, who had led the AFL for nearly forty years, for the Presidency of the AFL in 1921. William Green, one of his subordinates within the Mine Workers at the time, nominated him; William Hutcheson, the President of the Carpenters, supported him. Gompers won. Three years later, on Gompers' death, Green succeeded him as AFL President.
Thanks to the Wagner Act of 1935, labor union membership grew rapidly, especially in the coal mines. Lewis and the UMW were major backers of Franklin D. Roosevelt's reelection in 1936, and were firmly committed to the New Deal.
Lewis sent his best organizers into heavy industry in 1935-37, to organize the auto workers, the glass workers, the rubber workers and others. He supported the illegal sit-down strike (but did not use that tactic in the mines).
When the AFL balked at organizing unskilled workers, Lewis withdrew his unions and formed a new organization, the CIO. By 1937-40 the CIO was spending as much time fighting the AFL as organizing, with the result that union political power was divided against itself. During the late-1930s struggle over the AFL's refusal to organize mass production workers, Green became the target of some of Lewis' most stinging attacks while Hutcheson was the recipient of a famous punch from Lewis that came to symbolize the dispute between the conservative AFL and the rebellious CIO.
In the Presidential election of 1940, Lewis, heavily dependent on pro-Soviet organizers, rejected Roosevelt and supported Wendell Willkie, a Republican candidate, fearing Roosevelt's intention for American involvement in World War II. After the Japanese attack on Pearl Harbor the miners issued a no-strike pledge "for the duration" in support of the war effort. However, Lewis repeatedly violated the pledge, most notably in 1943 when half a million workers walked off the job. Public opinion was extremely angry and demanded new laws. President Roosevelt, a traditional ally of labor, felt he had no choice but to seize the mines. Even so, some steel mills closed for weeks and power shortages crippled production.
In the 1950s, Lewis won periodic wage and benefit increases for miners and led the campaign for the first Federal Mine Safety Act in 1952. Lewis tried to impose some order on a declining industry through collective bargaining, maintaining standards for his members by insisting that small operators agree to contract terms that effectively put many of them out of business. Mechanization nonetheless eliminated many of the jobs in his industry while scattered non-union operations persisted.
Lewis continued to be as autocratic as ever within the UMWA: until the passage of the Landrum-Griffin Act in 1959, the UMWA had kept a number of its districts in trusteeship for decades, meaning that Lewis appointed union officers who otherwise would have been elected by the membership.
Lewis retired as president of the UMWA in 1960 and was succeeded as president by Thomas Kennedy until his death in 1963, when he was succeeded by Lewis-anointed successor W.A. "Tony" Boyle, who was just as dictatorial, but without any of Lewis' leadership skills or vision.
Lewis purchased the "Lee-Fendall House", in Alexandria, Virginia in 1937. He resided here with his wife and daughter for 32 years until his death in 1969. He is buried in Oak Ridge Cemetery, Springfield, Illinois.