As he was growing up, Upton's family moved frequently, as his father was not successful in his career. He developed a love for reading when he was five years old. He read every book his mother owned for a deeper understanding of the world. He did not start school until he was 10 years old. He was deficient in math and worked hard to catch up quickly because of his embarrassment. In 1888, the Sinclair family moved to Queens, New York, where his father sold shoes. Upton entered the City College of New York five days before his 14th birthday, on September 15, 1892. He wrote jokes, dime novels, and magazine articles in boys' weekly and pulp magazines to pay for his tuition. With that income, he was able to move his parents to an apartment when he was seventeen years old.

He graduated in June 1897 and studied for a time at Columbia University. His major was law, but he was more interested in writing, and he learned several languages, including Spanish, German, and French. He paid the one-time enrollment fee to be able to learn a variety of things. He would sign up for a class and then later drop it. He again supported himself through college by writing boys' adventure stories and jokes. He also sold ideas to cartoonists. Using stenographers, he wrote up to 8,000 words of pulp fiction per day. His only complaint about his educational experience was that it failed to educate him about socialism. After leaving Columbia, he wrote four books in the next four years; they were commercially unsuccessful though critically well-received: King Midas (1901), Prince Hagen (1902), The Journal of Arthur Stirling (1903), and a Civil War novel titled Manassas (1904).

In April 1900, Sinclair went to Lake Massawippi in Quebec to work on a novel. He had a small cabin rented for three months and then he moved to a farmhouse. Here, his Future wife, Meta Fuller, and he became close. She was three years younger than him and had aspirations of being more than a housewife. Sinclair gave her direction as to what to read and learn. Meta had been a childhood friend whose family was one of the First Families of Virginia. Each had warned the other about themselves and would later bring that up in arguments. They married October 18, 1900. They used abstinence as their main form of birth control. Meta became pregnant with a child shortly after they married and attempted to abort it multiple times. The child was born on December 1, 1901, and named David. Meta and her family tried to get Sinclair to give up writing and get "a job that would support his family." Around 1911, Meta left Sinclair for the poet Harry Kemp, later known as the "Dunes Poet" of Provincetown, Massachusetts.

Sinclair's plan to end poverty quickly became a controversial issue under the pressure of numerous migrants to California fleeing the Dust Bowl. Conservatives considered his proposal an attempted communist takeover of their state and quickly opposed him, using propaganda to portray Sinclair as a staunch communist. Sinclair had been a member of the Socialist Party from 1902 to 1934, when he became a Democrat, though always considering himself a Socialist in spirit. The Socialist party in California and nationwide refused to allow its members to be active in any other party including the Democratic Party and expelled him, along with socialists who supported his California campaign. The expulsions destroyed the Socialist party in California.

In 1904, Sinclair spent seven weeks in disguise, working undercover in Chicago's meatpacking plants to research his novel, The Jungle (1906), a political exposé that addressed conditions in the plants, as well as the lives of poor immigrants. When it was published two years later, it became a bestseller.

His novel based on the meatpacking industry in Chicago, The Jungle, was first published in serial form in the socialist newspaper Appeal to Reason, from February 25, 1905, to November 4, 1905. It was published as a book by Doubleday in 1906.

Sinclair wrote in Cosmopolitan in October 1906 about The Jungle: "I aimed at the public's heart, and by accident I hit it in the stomach." The novel brought public lobbying for Congressional legislation and government regulation of the industry, including passage of the Meat Inspection Act and the Pure Food and Drug Act. At the time, President Theodore Roosevelt characterized Sinclair as a "crackpot", writing to william Allen White, "I have an utter contempt for him. He is hysterical, unbalanced, and untruthful. Three-fourths of the things he said were absolute falsehoods. For some of the remainder there was only a basis of truth." After reading The Jungle, Roosevelt agreed with some of Sinclair's conclusions, but was opposed to legislation that he considered "socialist". He said, "Radical action must be taken to do away with the efforts of arrogant and selfish greed on the part of the capitalist."

Sinclair was keenly interested in health and nutrition. He experimented with various diets, and with fasting. He wrote about this in his book, The Fasting Cure (1911), another bestseller. He believed that periodic fasting was important for health, saying, "I had taken several fasts of ten or twelve days' duration, with the result of a complete making over of my health".

Sinclair placed Budd within the important political events in the United States and Europe in the first half of the 20th century. An actual company named the Budd Company manufactured arms during World War II, founded by Edward G. Budd in 1912.

In 1913, Sinclair married Mary Craig Kimbrough (1883–1961), a woman from an elite Greenwood, Mississippi, family. She had written articles and a book on Winnie Davis, the daughter of Confederate States of America President Jefferson Davis. He met her when she attended a lecture by him about The Jungle. In the 1920s, the Sinclair couple moved to California. They were married until her death in 1961. Sinclair married again, to Mary Elizabeth Willis (1882–1967).

Sinclair broke with the Socialist party in 1917 and supported the war effort. By the 1920s, however, he had returned to the party.

In The Brass Check (1919), Sinclair made a systematic and incriminating critique of the severe limitations of the “free press” in the United States. Among the topics covered is the use of yellow journalism techniques created by william Randolph Hearst. Sinclair called The Brass Check "the most important and most dangerous book I have ever written."

In the 1920s, the Sinclairs moved to Monrovia, California, near Los Angeles, where Sinclair founded the state's chapter of the American Civil Liberties Union. Wanting to pursue politics, he twice ran unsuccessfully for United States Congress on the Socialist ticket: in 1920 for the House of Representatives and in 1922 for the Senate. He was the party candidate for governor California in 1930, winning nearly 50,000 votes.

During this period, Sinclair was also active in radical politics in Los Angeles. For instance, in 1923, to support the challenged free speech rights of Industrial Workers of the World, Sinclair spoke at a rally during the San Pedro Maritime Strike, in a neighborhood now known as Liberty Hill. He began to read from the Bill of Rights and was promptly arrested, along with hundreds of others, by the LAPD. The arresting officer proclaimed: "We'll have none of that Constitution stuff".

Aside from his political and social writings, Sinclair took an interest in occult phenomena and experimented with telepathy. His book Mental Radio (1930) included accounts of his wife Mary's telepathic experiences and ability. william McDougall read the book and wrote an introduction to it, which led him to establish the parapsychology department at Duke University.

This was a novel he published in 1934 as a preface to running for office. He outlined his plans in it.

After his loss to Merriam, Sinclair abandoned EPIC and politics to return to writing. In 1935, he published I, Candidate for Governor: And How I Got Licked, in which he described the techniques employed by Merriam's supporters, including the then popular Aimee Semple McPherson, who vehemently opposed socialism and what she perceived as Sinclair's modernism. Sinclair's line from this book "It is difficult to get a man to understand something, when his salary depends upon his not understanding it" has become well known and was for Example quoted by Al Gore in An Inconvenient Truth.

Between 1940 and 1953, Sinclair wrote a series of 11 novels featuring a central character named Lanny Budd. The son of an American arms manufacturer, Budd is portrayed as holding in the confidence of world Leaders, and not simply witnessing events, but often propelling them. As a sophisticated socialite, who mingles easily with people from all cultures and socioeconomic classes, Budd has been characterized as the antithesis of the stereotyped "Ugly American".

The novels were bestsellers upon publication and were published in translation, appearing in 21 countries. The third book in the series, Dragon's Teeth (1942), won the Pulitzer Prize for the Novel in 1943. Out of print and nearly forgotten for years, ebook editions of the Lanny Budd series were published in 2016.

Of his gubernatorial bid, Sinclair remarked in 1951:

Late in life Sinclair, with his third wife Mary Willis, moved to Buckeye, Arizona. They returned east to Bound Brook, New Jersey. Sinclair died there in a nursing home on November 25, 1968, a year after his wife. He is buried in Rock Creek Cemetery in Washington, DC, next to Willis.

Sinclair was born in Baltimore, Maryland, to Upton Beall Sinclaira and Priscilla Harden Sinclair. His father was a liquor salesman whose alcoholism shadowed his son's childhood. Priscilla Harden Sinclair was a strict Episcopalian who disliked alcohol, tea, and coffee. As a child, Sinclair slept either on sofas or cross-ways on his parents' bed. When his father was out for the night, he would sleep alone in the bed with his mother. Sinclair did not get along with her when he became older because of her strict rules and refusal to allow him independence. Sinclair later told his son, David, that around Sinclair's 16th year, he decided not to have anything to do with his mother, staying away from her for 35 years because an argument would start if they met. His mother's family was very affluent: her parents were very prosperous in Baltimore, and her sister married a millionaire. Sinclair had wealthy maternal grandparents with whom he often stayed. This gave him insight into how both the rich and the poor lived during the late 19th century. Living in two social settings affected him and greatly influenced his books. Upton Beall Sinclair, Sr., was from a highly respected family in the South, but the family was financially ruined by the Civil War, disruptions of the labor system during the Reconstruction era, and an extended agricultural depression.