De Leon settled in New York, studying at Columbia University. He became a committed socialist and in 1890 joined the Socialist Labor Party, (SLP) becoming the editor of its newspaper, The People. He quickly grew in stature inside the party and in 1891 he ran for the governorship of the state of New York, winning 13,000 votes in the process.
De Leon was highly critical of the trade union movement in America. Originally a member of the Knights of Labor, he helped form the Socialist Trade and Labor Alliance (STLA) in 1895 as a radical alternative to the American Federation of Labour.
By the early 20th century the SLP was declining in influence, with firstly the Social Democratic Party and then the Socialist Party of America becoming the leading leftist political force in America. However, De Leon remained an important figure in the US labor movement, and in 1905 he helped found the Industrial Workers of the World (IWW).
De Leon lost control and the ability to influence the organisation to Bill Haywood and left the IWW to form a rival IWW which was soon renamed as the Workers' International Industrial Union. He died in New York in 1914.