While at a country club, Fitzgerald met Zelda Sayre (1900–1948), the "golden girl", in Fitzgerald's words, of Montgomery, Alabama, youth society. The two were engaged in 1919, and Fitzgerald moved into an apartment at 1935 Lexington Avenue in New York City to try to lay a foundation for his life with Zelda. Working at an advertising firm and writing short stories, he was unable to convince Zelda that he would be able to support her, leading her to break off the engagement. Scott returned to his parents' house at 599 Summit Avenue, on Cathedral Hill, in St. Paul, to revise The Romantic Egoist. Recast as This Side of Paradise, about the post-WWI flapper generation, it was accepted by Scribner's in the fall of 1919, and Zelda and Scott resumed their engagement. The novel was published on March 26, 1920, and became one of the most popular books of the year. Scott and Zelda were married in New York's St. Patrick's Cathedral. Their only child, Frances Scott "Scottie" Fitzgerald, was born on October 26, 1921.

The 1920s proved the most influential decade of Fitzgerald's development. The Great Gatsby, considered his masterpiece, was published in 1925. Fitzgerald made several excursions to Europe, notably Paris and the French Riviera, and became friends with many members of the American expatriate community in Paris, notably Ernest Hemingway. Fitzgerald’s friendship with Hemingway was quite vigorous, as many of Fitzgerald’s relationships would prove to be. Hemingway did not get on well with Zelda. In addition to describing her as "insane" he claimed that she “encouraged her husband to drink so as to distract Scott from his ‘real’ work on his novel," the other work being the short stories he sold to magazines. This “whoring”, as Fitzgerald, and subsequently Hemingway, called these sales, was a sore point in the authors’ friendship. Fitzgerald claimed that he would first write his stories in an authentic manner but then put in “twists that made them into saleable magazine stories.”

Fitzgerald's marriage was mixed—both destructive and constructive. Fitzgerald drew largely upon his wife's intense and flamboyant personality in his writings, at times quoting direct passages from her letters and personal diaries in his work. Zelda made mention of this in a 1922 mock review in the New York Tribune, saying that "[i]t seems to me that on one page I recognized a portion of an old diary of mine which mysteriously disappeared shortly after my marriage, and also scraps of letters which, though considerably edited, sound to me vaguely familiar. In fact, Mr. Fitzgerald — I believe that is how he spells his name — seems to believe that plagiarism begins at home" (Zelda Fitzgerald: The Collected Writings, 388). But the impact of Zelda's personality on his work and life is often overstated, as much of his earliest writings reflect the personality of a first love, Ginevra King. In fact, the character of Daisy as much represents his inability to cultivate his relationship with King as it does the ever-present fact of Zelda. (Although Gatsby's economic failure to immediately wed Daisy in 1917, with an eventual return in financial triumph, does closely mirror Fitzgerald's own experiences with his future wife).

Although Fitzgerald's passion lay in writing novels, only his first novel sold well enough to support the opulent lifestyle that he and Zelda adopted as New York celebrities. As did most professional authors at the time, Fitzgerald supplemented his income by writing short stories for such magazines as The Saturday Evening Post, Collier's Weekly, and Esquire, and sold movie rights of his stories and novels to Hollywood studios. Many of these stories act as testing grounds for his novels. For example, "Absolution" was intended as an earlier chapter in The Great Gatsby. Because of this lifestyle, as well as the bills from Zelda's medical care when they came, Fitzgerald was constantly in financial trouble and often required loans from his literary agent, Harold Ober, and his editor at Scribner's, Maxwell Perkins. When Ober decided not to continue advancing Fitzgerald, the author severed ties with his longtime friend and agent. (Fitzgerald offered a good-hearted and apologetic tribute to this support in the late short story "Financing Finnegan").

Fitzgerald began working on his fourth novel during the late 1920s but was sidetracked by financial difficulties that necessitated his writing commercial short stories, and by the schizophrenia that struck Zelda in 1930. Her emotional health remained fragile for the rest of her life. In 1932, she was hospitalized in Baltimore, Maryland. Scott rented the "La Paix" estate in the suburb of Towson, Maryland, to work on his latest book, the story of the rise and fall of Dick Diver, a promising young psychiatrist who falls in love with and marries Nicole Warren, one of his patients. The book went through many versions, the first of which was to be a story of matricide. Some critics have seen the book as a thinly-veiled autobiographical novel recounting Fitzgerald's problems with his wife, the corrosive effects of wealth and a decadent lifestyle, his own egoism and self-confidence, and his continuing alcoholism. Indeed, Fitzgerald was extremely protective of his material (their life together). When Zelda wrote and sent to Scribner's her own fictional version of their lives in Europe, Save Me the Waltz, Fitzgerald was angry and was able to make some changes prior to the novel's publication, and convince her doctors to keep her from writing any more about what he called his "material," which included their relationship. His book was finally published in 1934 as Tender Is the Night. Critics who had waited nine years for the followup to The Great Gatsby had mixed opinions about the novel. Most were thrown off by its three-part structure and many felt that Fitzgerald had not lived up to their expectations. The novel did not sell well upon publication, but like the earlier Gatsby, the book's reputation has since risen significantly.

Although he reportedly found movie work degrading, Fitzgerald was once again in dire financial straits, and spent the second half of the 1930s in Hollywood, working on commercial short stories, scripts for Metro-Goldwyn-Mayer (including some unfilmed work on Gone with the Wind), and his fifth and final novel, The Love of the Last Tycoon. Published posthumously as The Last Tycoon, it was based on the life of film executive Irving Thalberg. Scott and Zelda became estranged; she continued living in mental institutions on the East Coast, while he lived with his lover Sheilah Graham, a gossip columnist, in Hollywood. From 1939 until his death, Fitzgerald mocked himself as a Hollywood hack through the character of Pat Hobby in a sequence of 17 short stories, later collected as "The Pat Hobby Stories."

Fitzgerald had been an alcoholic since his college days, and became notorious during the 1920s for his extraordinarily heavy drinking, leaving him in poor health by the late 1930s. According to Zelda's biographer, Nancy Milford, Scott claimed that he had contracted tuberculosis, but Milford dismisses it as a pretext to cover his drinking problems. However, Fitzgerald scholar Matthew J. Bruccoli contends that Fitzgerald did in fact have recurring tuberculosis, and Nancy Milford reports that Fitzgerald biographer Arthur Mizener said that Scott suffered a mild attack of tuberculosis in 1919, and in 1929 he had "what proved to be a tubercular hemorrhage". It has been said that the hemorrhage was caused by bleeding from esophageal varices.

Fitzgerald suffered two heart attacks in late 1940. After the first, in Schwab's Drug Store, he was ordered by his doctor to avoid strenuous exertion. He moved in with Sheilah Graham, who lived in Hollywood on North Hayworth Ave., one block east of Fitzgerald's apartment on North Laurel Ave. Fitzgerald had two flights of stairs to get to his apartment; Graham's was a ground floor apartment. On the night of December 20, 1940, Fitzgerald and Sheilah Graham attended the premiere of "This Thing Called Love" starring Melvyn Douglas and Rosalind Russell. As the two were leaving the Pantages Theater, Fitzgerald experienced a dizzy spell and had trouble leaving the theater; upset, he said to Ms. Graham, "They think I am drunk, don't they?". The following day, as Scott ate a candy bar and made notes in his newly arrived Princeton Alumni Weekly, Ms. Graham saw him jump from his armchair, grab the mantelpiece, gasp, and fall to the floor. She ran to the manager of the building, Harry Culver, founder of Culver City; upon entering the apartment and assisting Scott, he stated, "I'm afraid he's dead." Fitzgerald died of a massive heart attack. His body was removed to the Pierce Brothers Mortuary.

Among the attendants at a visitation held at a funeral home was Dorothy Parker, who reportedly cried and murmured "the poor son-of-a-bitch," a line from Jay Gatsby's funeral in Fitzgerald's The Great Gatsby. The remains were shipped to Baltimore, Maryland, where his funeral was attended by twenty or thirty people in Bethesda; among the attendants were his only child, Frances "Scottie" Fitzgerald Lanahan Smith, and his editor, Maxwell Perkins. Fitzgerald was originally buried in Rockville Union Cemetery. Zelda died in 1948, in a fire at the Highland Mental Hospital in Asheville, North Carolina. Ms. Frances Lanahan worked to overturn the Archdiocese of Baltimore ruling that Fitzgerald died a non practicing Catholic, so that he could be at rest at the Roman Catholic cemetery where his father's family was laid. Both Scott's and Zelda's remains were moved to the family plot in Saint Mary's Cemetery, in Rockville, Maryland, in 1975.

Fitzgerald died before he could complete The Love of the Last Tycoon. His manuscript, which included extensive notes for the unwritten part of the novel's story, was edited by his friend, the literary critic Edmund Wilson, and published in 1941 as The Last Tycoon. In 1994 the book was reissued under the original title The Love of the Last Tycoon, which is now agreed to have been Fitzgerald's preferred title.