Tresca settled in Philadelphia, where he became the editor of Il Proletario (The Proletarian), the official newspaper of the Italian Socialist Federation (ISF). Tresca helped shift the political orientation of the ISF to syndicalism, and, as his own views became more anarchist, Tresca resigned as editor of Il Proletario and began publshing his own newspaper La Plebe (The Plebs). He would later transfer La Plebe to Pittsburgh and, with it, revolutionary ideas to Italian miners and mill workers in Western Pennsylvania.
Tresca joined the Industrial Workers of the World (IWW) in 1912, when he was invited by the union to Lawrence, Massachusetts to help mobilize the Italian workers during a campaign to free strike leaders Joseph Ettor and Arturo Giovannitti, who were in prison on false murder charges.
After the victorious strike in Lawrence, Tresca was active in strikes across the United States: the Little Falls, New York textile workers' strike (1912), the New York City hotel workers' strike (1913), the Paterson, New Jersey silk workers' strike (1913), and the Mesabi Range, Minnesota, miners strike (1916).
Tresca became a major figure among Italian-Americans in trying to halt Benito Mussolini's attempts to organize Italian immigrants into fascist support groups. At this time, Tresca was editing an anti-fascist newspaper named Il Martello (The Hammer), where he blasted Mussolini as a class enemy and traitor. Tresca's anti-fascist activities were being monitored in Rome, while, in the U.S., Tresca was under heavy surveillance from the American government. In 1926, fascists attempted to assassinate Tresca with a bomb during a rally.
Shortly thereafter, in the 1930's, Tresca became outspoken against Communists and Stalinism, particularly after Stalinists had destroyed the anarchist movement in Catalonia and Aragon during the Spanish Revolution. Prior to this, Tresca had supported the Bolsheviks, reasoning that a socialist state was preferable to a capitalist state, regarding the Communists as allies in the fight against fascism.
In 1943, Tresca was assassinated, a murder which remains officially unresolved. Suspects include fascists, communist agents and underworld mafia figures.