After beginning his career as a corporations lawyer in Illinois, he switched sides to represent the American Railway Union, led by Eugene V. Debs, in the Pullman Strike of 1894. Following that he successfully defended Big Bill Haywood, leader of the Industrial Workers of the World and the Western Federation of Miners, on charges of murdering the former governor of Idaho in 1905. He was not so successful when called on to defend the MacNamara Brothers, who were charged with dynamiting the Los Angeles Times building as part of the bitter struggle over the open shop in Southern California: Darrow convinced them to plead guilty and barely escaped conviction himself for his clumsy attempt to bribe a juror.
A story often told about Darrow is his quip to a client, who, after winning a case, said, "How can I ever show my appreciation, Mr. Darrow?" Darrow replied, "Ever since the Phoenicians invented money, there has been only one answer to that question." Darrow shared offices with Edgar Lee Masters, who achieved more fame for his poetry, in particular the Spoon River Anthology, than for his advocacy.