Clarence Darrow was born in the small town of Kinsman, Ohio, on April 18, 1857, the fifth son of Amirus and Emily Darrow (née Eddy). Both the Darrow and Eddy families had deep roots in colonial New England, and several of Darrow's ancestors served in the American Revolution. Darrow's father was an ardent abolitionist and a proud iconoclast and religious freethinker. He was known throughout the town as the "village infidel". Emily Darrow was an early supporter of female suffrage and a women's rights advocate.

The young Clarence attended Allegheny College and the University of Michigan Law School, but did not graduate from either institution. He attended Allegheny College for only one year before the Panic of 1873 struck, and Darrow was determined not to be a financial burden to his father any longer. Over the next three years he taught in the winter at the district school in a country community. While teaching, Darrow started to study the law on his own, and by the end of his third year of teaching, his family urged him to enter the law department at Ann Arbor. Darrow only studied there a year when he decided that it would be much more cost-effective to work and study in an actual law office. When he felt that he was ready, he took the Ohio bar exam and passed. He was admitted to the Ohio bar in 1878. The Clarence Darrow Octagon House, his childhood home in Kinsman, contains a memorial to him.

In 1880, he married Jessie Ohl, and eight years later he moved to Chicago with his wife and young son, Paul. He did not have much Business when he first moved to Chicago, and spent as little as possible. He joined the Henry George Club and made some friends and connections in the city. Being part of the club also gave him an opportunity to speak for the Democratic Party on the upcoming election. He slowly made a name for himself through these speeches, eventually earning the standing to speak in whatever hall he liked. He was offered work as an attorney for the city of Chicago. Darrow worked in the city law department for two years when he resigned and took a position as a Lawyer at the Chicago and North-Western Railway Company. In 1894, Darrow represented Eugene V. Debs, the leader of the American Railway Union, who was prosecuted by the federal government for leading the Pullman Strike of 1894. Darrow severed his ties with the railroad to represent Debs, making a financial sacrifice. He saved Debs in one trial but could not keep him from being jailed in another.

Also in 1894, Darrow took on the first murder case of his career, defending Patrick Eugene Prendergast, the "mentally deranged drifter" who had confessed to murdering Chicago mayor Carter Harrison, Sr. Darrow's "insanity defense" failed and Prendergast was executed that same year. Among fifty defenses in murder cases throughout the whole of Darrow's career, the Prendergast case would prove to be the only one resulting in an execution, though Darrow did not join the defense team until after Prendergast's conviction and sentence, in an effort to spare him the noose.

Darrow soon became one of America's leading labor attorneys. He helped organize the Populist Party in Illinois and then ran for U.S. Congress as a Democrat in 1895 but lost to Hugh R. Belknap. In 1897, his marriage to Jessie Ohl ended in divorce. He joined the Anti-Imperialist League in 1898 in opposition to the U.S. annexation of the Philippines. He represented the woodworkers of Wisconsin in a notable case in Oshkosh in 1898 and the United Mine Workers in Pennsylvania in the great anthracite coal strike of 1902. He flirted with the idea of running for mayor of Chicago in 1903 but ultimately decided against it. The following year, in July, Darrow married Ruby Hammerstrom, a young Chicago Journalist. His former mentor, Governor John Peter Altgeld, joined Darrow's firm following his Chicago mayoral electoral defeat in 1899 and worked with Darrow until his death in 1902.

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

From 1906 to 1908, Darrow represented the Western Federation of Miners Leaders william "Big Bill" Haywood, Charles Moyer, and George Pettibone when they were arrested and charged with conspiring to murder former Idaho Governor Frank Steunenberg in 1905. After a series of trials, Haywood and Pettibone were found not guilty and the charges against Moyer were dropped.

In 1911, the American Federation of Labor (AFL) called on Darrow to defend the McNamara brothers, John and James, who were charged in the Los Angeles Times bombing on October 1, 1910, during the bitter struggle over the open shop in Southern California. The bomb had been placed in an alley behind the building, and although the explosion itself did not bring the building down, it ignited nearby ink barrels and natural gas main lines. In the ensuing fire, 20 people were killed. The AFL appealed to local, state, regional and national unions to donate 25 cents per capita to the defense fund, and set up defense committees in larger cities throughout the nation to accept donations.

The defense's position weakened when, on November 28, Darrow was accused of orchestrating to bribe a prospective juror. The juror reported the offer to police, who set up a sting and observed the defense team's chief investigator, Bert Franklin, delivering $4,000 to the juror two blocks away from Darrow's office. After making payment, Franklin walked one block in the direction of Darrow's office before being arrested right in front of Darrow himself, who had just walked to that very intersection after receiving a phone call in his office. With Darrow himself on the verge of being discredited, the defense's hope for a simple plea agreement ended. On December 1, 1911, the McNamara brothers changed their pleas to guilty, in open court. The plea bargain Darrow helped arrange earned John fifteen years and James life imprisonment. Despite sparing the brothers the death penalty, Darrow was accused by many in organized labor of selling the movement out.

In the November 18, 1915 edition of The Washington Post, Darrow stated: “Chloroform unfit children. Show them the same mercy that is shown beasts that are no longer fit to live.” However, Darrow was also critical of some eugenics advocates.

Darrow's closing argument lasted 12 hours. He repeatedly stressed the ages of the "boys" (before the Vietnam War, the age of majority was 21) and noted that "never had there been a case in Chicago where on a plea of guilty a boy under 21 had been sentenced to death." His plea was designed to soften the heart of Judge John Caverly, but also to mold public opinion, so that Caverly could follow precedent without too huge an uproar. Darrow succeeded. Caverly sentenced Leopold and Loeb to life in prison plus 99 years. Darrow's closing argument was published in several editions in the late 1920s and early 1930s, and was reissued at the time of his death.

In the summer of 1924, Darrow took on the case of Nathan Leopold Jr. and Richard Loeb, the teenage sons of two wealthy Chicago families who were accused of kidnapping and killing Bobby Franks, a 14-year-old boy, from their stylish southside Kenwood neighborhood. Leopold was a law student at the University of Chicago about to transfer to Harvard Law School, and Loeb was the youngest graduate ever from the University of Michigan; they were 18 and 17, respectively, when they were arrested. When asked why they committed the crime, Leopold told his captors: "The thing that prompted Dick to want to do this thing and prompted me to want to do this thing was a sort of pure love of excitement... the imaginary love of thrills, doing something different... the satisfaction and the ego of putting something over."

On September 9, 1925, a white mob in Detroit attempted to drive a black family out of the home they had purchased in a white neighborhood. During the struggle, a white man was killed, and the eleven black men in the house were later arrested and charged with murder. Dr. Ossian Sweet and three members of his family were brought to trial, and after an initial deadlock, Darrow argued to the all-white jury: "I insist that there is nothing but prejudice in this case; that if it was reversed and eleven white men had shot and killed a black man while protecting their home and their lives against a mob of blacks, nobody would have dreamed of having them indicted. They would have been given medals instead...."

In January 1931 Darrow had a debate with English Writer G. K. Chesterton during the latter's second trip to America. This was held at New York City's Mecca Temple. The topic was "Will the World Return to Religion?". At the end of the debate those in the hall were asked to vote for the man they thought had won the debate. Darrow received 1,022 votes while Chesterton received 2,359 votes. There is no known transcript of what was said except for third party accounts published later on. The earliest of these was that of February 4, 1931, issue of The Nation with an article written by Henry Hazlitt.

The Scopes Trial and the Sweet trial were the last big cases that Darrow took on before he retired from full-time practice at the age of 68. He still took on a few cases such as the 1932 Massie Trial in Hawaii.

Darrow died on March 13, 1938 of pulmonary heart disease. He was 80 years old.

In the weeks before the jury was seated, Darrow became increasingly concerned about the outcome of the trial and began negotiations for a plea bargain to spare the defendants' lives. During the weekend of November 19–20, 1911, he discussed with pro-labor Journalist Lincoln Steffens and newspaper publisher E.W. Scripps the possibility of reaching out to the Times about the terms of a plea agreement. The prosecution had demands of its own, however, including an admission of guilt in open court and longer sentences than the defense proposed.

The event led to a change in public sentiment and an increased discourse on the creation claims of religious teachers versus those of secular Scientists — i.e., creationism compared to evolutionism — that still exist. It also became popularized in a play based loosely on the trial, Inherit the Wind, which has been adapted several times on film and television.

During the trial, the newspapers claimed that Darrow was presenting a "million dollar defense" for the two wealthy families. Many ordinary Americans were angered at his apparent greed. He had the families issue a statement insisting that there would be no large legal fees and that his fees would be determined by a committee composed of officers from the Chicago Bar Association. After trial, Darrow suggested $200,000 would be reasonable. After lengthy negotiations with the defendants' families, he ended up getting some $70,000 in gross fees, which, after expenses and taxes, netted Darrow $30,000, worth over $375,000 in 2016.