While she was in South Carolina, a friend of hers showed some of her paintings to the photographer and art gallery owner Alfred Stieglitz, who was impressed by her work. After some negotiations, O'Keeffe allowed Stieglitz to exhibit her. Stieglitz was especially impressed with O'Keeffe's paintings of landscapes in the American West. Eventually, Stieglitz arranged for O'Keeffe to move to New York City, securing a place for her to live. Over the next few years O'Keeffe and Stieglitz spent more time together. In 1924, Stieglitz's wife, from who he'd been separated for many years, finally gave him a divorce, and he and O'Keeffe were married.

During her years in New York City, O'Keefe produced many fine paintings, including urban and architectural images. With Stieglitz connections in the arts community of New York, O'Keefe's work received a great deal of attention and commanded high prices. Yet O'Keeffe tired of the scene in New York and took the opportunity to spend increasing amounts of time in the west. Stieglitz, who was many years older and often in ill health, was uncomfortable with travel, which meant her trips west gave her the solitude she required to pursue her art.

O'Keeffe spent much of her time in Taos, New Mexico, and when Stieglitz died in 1946, she took up permanent residence there, living in Taos or Santa Fe until her death in 1986. Her home was in Abiqui, NM. O'Keeffe is known chiefly for her landscapes and paintings of desert flowers, which are often interpreted as yonic symbols. Her Mature style stressed contours and subtle tonal transitions, which often transformed the subject into a powerful abstract image.