From Corporate Lawyer to Labor Lawyer
Darrow began his career as a lawyer in Youngstown, Ohio, where he was first admitted to the profession (Judge Alfred W. Mackey). He subsequently moved to Chicago, Illinois, where he soon became a corporations lawyer for the railroad company. His next move was to "cross the tracks," when he switched sides to represent Eugene V. Debs, the leader of the American Railway Union in the Pullman Strike of 1894. Darrow had conscientiously resigned his corporate position in order to represent Debs, making a substantial financial sacrifice in order to do this, although the work was not pro bono.

Darrow defended Haywood, the radical leader of the Industrial Workers of the World and the Western Federation of Miners, who was acquitted of charges of being involved in the murder of former Idaho governor Frank Steunenberg in 1905. His next notable case was the defense of the MacNamara Brothers, who were charged with dynamiting the Los Angeles Times building during the bitter struggle over the open shop in Southern California, resulting in the deaths of 20 employees.

When Darrow saw the weight of the evidence against the brothers he convinced them to change their plea to guilty and was able to plea bargain prison sentences instead of the death penalty. However Darrow himself was subsequently charged with two counts of attempting to bribe jurors in the MacNamara case, and although he was acquitted on both charges he was barred from ever practicing law in California again.

From Labor Lawyer to Criminal Lawyer
A further consequence of the bribery charges was that the labor unions dropped Darrow from their list of preferred attorneys. This effectively put Darrow out of business as a labor lawyer, and he switched to acting in criminal cases.

Throughout his career, Darrow devoted himself to opposing the death penalty, which he felt to be in conflict with humanitarian progress. In more than 100 cases, Darrow only lost one murder case in Chicago. He became renowned for moving juries and even judges to tears with his eloquence. Despite scant education, which included a year at the University of Michigan Law School, Darrow had a keen intellect often shielded by his rumpled, unassuming appearance.

A story attributed to Darrow is his quip to a client, who, after winning, 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." Indeed, Darrow's pursuit of wealth is often cited by his detractors, and it is notable that in his entire legal career Darrow only ever accepted one pro bono case - John Scopes of the Scopes Monkey Trial fame.
Even on that one occasion Darrow acted from necessity. He badly wanted to take part in the trial, but Scopes was in no position to pay him, and the ACLU, who were paying all of Scopes' legal costs, didn't want Darrow involved in the trial and certainly wouldn't have agreed to pay him.

Leopold and Loeb
In 1924 Darrow took on the case of Leopold and Loeb, the teenage sons of two wealthy Chicago families, who were accused of kidnapping and killing Bobby Franks, a 14 year old boy, to see what it would be like to commit the ultimate crime. Darrow convinced them to plead guilty and based their defense on the claim that they weren't completely responsible for their actions, but were the products of the environment they grew up in. This was done in order to avoid the death penalty. During the Leopold-Loeb trial, when Darrow had supposedly accepted "a million-dollar fee", many ordinary Americans were angered at their apparent betrayal. In truth, Darrow and his two co-counsels were given $100,000 to split three ways— after dunning the wealthy Loeb family for several months.

Ossian Sweet
In 1925, he defended Henry Sweet, a young black man living in Detroit with his brother, Dr. Ossian Sweet, in the shooting death of a member of a white mob. The mob of at least a 1,000 people had gathered outside Dr. Sweet's home to force him to move from the neighborhood. Eleven people were originally charged with the murder, and after the first trial ended in a mistrial, Darrow requested separate trials for each defendant and Henry Sweet's was the first. Darrow referred to the trial as one of his best argued, finishing with a legendary eight-hour impassioned closing argument which won acquittal for Henry Sweet from the eleven-man jury, shocking the city. Following the acquittal, charges against the remaining defendants were dropped.

After the 1925 Scopes Trial, Clarence Darrow largely retired from practice, emerging only occasionally to undertake cases, such as the 1934 Massie Trial in Hawaii.

A volume of Darrow's boyhood Reminiscences, entitled "Farmington," was published in Chicago in 1903 by McClurg and Company.

Darrow shared offices with Edgar Lee Masters, who achieved more fame for his poetry, in particular the Spoon River Anthology, than for his advocacy. Darrow also took Eugene V. Debs as a partner, following his release from prison.

After his death, a full-length one man play was created, featuring Darrow's reminiscences about his career. Originated by Henry Fonda, many actors, including Leslie Nielsen, have since taken on the role of Darrow in this play. The Scopes Monkey trials were fictionalized in another play, entitled "Inherit the Wind." This was later turned into a film. Darrow is also mentioned in the musical, "Lil Abner".