In 1900, Durant was educated by the Jesuits in St. Peter's Preparatory School and, later, Saint Peter's College in Jersey City, New Jersey. Historian Joan Rubin writes of that period, "Despite some adolescent flirtations, he began preparing for the vocation that promised to realize his mother's fondest hopes for him: the priesthood. In that way, one might argue, he embarked on a course that, while distant from Yale's or Columbia's apprenticeships in gentility, offered equivalent cultural authority within his own milieu."

In 1905, he began experimenting with socialist philosophy, but, after World War I, he began recognizing that a "lust for power" underlay all forms of political behavior. However, even before the war, "other aspects of his sensibility had competed with his radical leanings," notes Rubin. She adds that "the most concrete of those was a persistent penchant for philosophy. With his Energy invested in Baruch Spinoza, he made little room for the Russian anarchist Mikhail Bakunin. From then on, writes Rubin, "his retention of a model of selfhood predicated on discipline made him unsympathetic to anarchist injunctions to 'be yourself.'... To be one's 'deliberate self,' he explained, meant to 'rise above' the impulse to 'become the slaves of our passions' and instead to act with 'courageous devotion' to a moral cause."

Durant graduated in 1907. He worked as a reporter for Arthur Brisbane's New York Evening Journal for 10 dollars a week. At the Evening Journal, he wrote several articles on sexual Criminals. In 1907, he began teaching Latin, French, English and geometry at Seton Hall University, South Orange, New Jersey. He was also made librarian there.

In 1911, he left the seminary. He became the principal of Ferrer Modern School, an advanced school intended to educate the working classes; he also taught there. Alden Freeman, a supporter of the Ferrer Modern School, sponsored him for a tour of Europe. At the Modern School, he fell in love with and married a 15-year-old pupil, Chaya (Ida) Kaufman, whom he later nicknamed "Ariel". The Durants had one daughter, Ethel, and adopted a son, Louis.

In 1913, he resigned his post as Teacher. To support themselves, he began lecturing in a Presbyterian church for $5 and $10; the material for the lectures became the starting point for The Story of Civilization.

By 1914, he began to reject "intimations of human evil", notes Rubin, and to "retreat from radical social change." She summarizes the changes in his overall philosophy:

In 1917, while working on a doctorate in philosophy at Columbia University, he wrote his first book, Philosophy and the Social Problem. He discussed the idea that philosophy had not grown because it avoided the actual problems of society. He received his doctorate that same year from Columbia. He was also an instructor at the university.

The Story of Philosophy originated as a series of Little Blue Books (educational pamphlets aimed at workers) and was so popular it was republished in 1926 by Simon & Schuster as a hardcover book and became a bestseller, giving the Durants the financial independence that would allow them to travel the world several times and spend four decades writing The Story of Civilization. Will left teaching and began work on the 11-volume Story of Civilization.

In an article in 1927, he wrote his thoughts about reconciling religion and Darwinism:

In 1930, he published The Case for India while he was on a visit to India as part of collecting data for The Story of Civilization. He was so taken aback by the devastating poverty and starvation he saw as a result of British imperial policy in India that he took time off from his stated goal and instead concentrated on his polemic fiercely advocating Indian independence.

In 1933, he published Tragedy of Russia: Impressions from a Brief Visit and soon afterward The Lesson of Russia. A few years after the books were published, social commentator Will Rogers had read them and described a symposium he had attended that included Durant as one of the contributors. He later wrote of Durant, "He is just about our best Writer on Russia. He is the most fearless Writer that has been there. He tells you just what it's like. He makes a mighty fine talk. One of the most interesting lecturers we have, and a fine fellow."

The first volume of The Story of Civilization series, called Our Oriental Heritage (1935), is divided into an introduction and three books. The introduction takes the reader through the different aspects of civilization (economical, political, moral and mental). Book One is dedicated to the civilizations of the Near East (Sumeria, Egypt, Babylonia, Assyria, Judea and Persia). Book two is "India and Her Neighbors." Book three moves deeper into the east, where the Chinese Civilization flourishes and Japan starts to find its place in the world's political map.

On April 8, 1944, Durant was approached by two Leaders of the Jewish and Christian faiths, Meyer David and Christian Richard about starting "a movement, to raise moral standards." He suggested instead that they start a movement against racial intolerance and outlined his ideas for a "Declaration of Interdependence". The movement for the declaration, Declaration of INTERdependence, Inc., was launched at a gala dinner at the Hollywood Roosevelt Hotel on March 22, 1945, attended by over 400 people including Thomas Mann and Bette Davis. The Declaration was read into the Congressional Record on October 1, 1945, by Ellis E. Patterson.

Throughout his career, Durant made several speeches, including "Persia in the History of Civilization", which was presented as an address before the Iran-America Society in Tehran, Iran, on April 21, 1948 and had been intended for inclusion in the Bulletin of the Asia Institute (formerly, Bulletin of the American Institute for Persian, then Iranian, Art and Archaeology), Vol. VII, no. 2, which never saw publication.

For Rousseau and Revolution (1967), the 10th volume of The Story of Civilization, the Durants were awarded the Pulitzer Prize for literature. In 1977, it was followed by one of the two highest awards granted by the United States government to civilians, the Presidential Medal of Freedom, awarded by Gerald Ford.

The Durants were awarded the Pulitzer Prize for General Non-Fiction in 1968 and the Presidential Medal of Freedom in 1977.

Though Ariel and Will had intended to carry the work on The Story of Civilisation into the 20th century, at their now very advanced age they expected the 10th volume to be their last. However, they went on to publish a final volume, their 11th, The Age of Napoleon in 1975. They also left behind notes for a 12th volume, The Age of Darwin, and an outline for a 13th, The Age of Einstein, which would have taken The Story of Civilization to 1945.

The Durants also shared an intense love for one another as explained in their Dual Autobiography. After Will entered the hospital, Ariel stopped eating, and died on October 25, 1981. Though their daughter, Ethel, and grandchildren strove to keep Ariel's death from the ailing Will, he learned of it on the evening news, and died two weeks later, at the age of 96, on November 7, 1981. Will was buried beside Ariel in Westwood Village Memorial Park Cemetery, in Los Angeles.

Three posthumous works by Durant have been published in recent years, The Greatest Minds and Ideas of All Time (2002), Heroes of History: A Brief History of Civilization from Ancient Times to the Dawn of the Modern Age (2001), and Fallen Leaves (2014).

More than twenty years after his death, a quote from Durant, "A great civilization is not conquered from without until it has destroyed itself within" appeared as the opening graphic of Mel Gibson's 2006 film Apocalypto. Durant also served as the history consultant for Anthony Mann's 1964 film The Fall of the Roman Empire. The narration at the beginning and the end of the film is taken almost directly from Durant's work Caesar and Christ.