O’Keeffe’s arrival in New York marked the beginning of her romantic relationship with Alfred Stieglitz. At first, Stieglitz supported her by finding her a place to stay, and more importantly a place to work. Their relationship grew stronger as a result of their mutual love for art and interaction between their respective arts. Georgia respected Stieglitz, was pleased by his praise, and learned much by interacting with the other artists he worked with. However, her artwork was still primarily focused on her own needs and expressions.

Already a famous photographer, Stieglitz started photographing O’Keeffe and would eventually produce about 300 portraits of her between 1918 and 1937. One photography session in particular brought them closer together. Stieglitz had invited Georgia to his apartment while his wife, Emmeline, was shopping. He proceeded to take several nude photographs of Georgiaa, but their session was interrupted by the return of Emmeline, who was enraged and demanded that Stieglitz move out of the apartment. His marriage with Emmeline had always been strained: he was not interested in what he saw as her superficial social aspirations in elite society, and she never mixed with his artist colleagues. Therefore, the break was somewhat of a relief for Stieglitz, who had felt restricted under his wife’s domain. With Georgia he shared a passion for art and a persistent sexual drive, which presented itself in both of their works.

Stieglitz assisted O’Keeffe in establishing her artistic career by organizing exhibits and selling her artwork at soaring prices. As a result, her reputation flourished, and her relationship with Stieglitz deepened. Moreover, O’Keeffe’s prestige and notoriety in the art world mounted as her first major exhibition, in January of 1923, attracted 500 people on the first day. The 100 featured watercolors, charcoals, drawings, and oil paintings were mostly still-lifes, abstractions, and paintings of Lake George, such as Lake George With Crows (1921). Although O’Keeffe’s art was similar to that of Marsden Hartley and Arthur Dove, her position as a woman in the modern art world attracted much attention, leading critics to interpret her differences from other artists as resulting from her femininity. Moreover, her use of radiant colors and her style of painting presented many viewers with obvious sexual imagery and emotion. According to one critic, Paul Rosenfeld:

"What men have always wanted to know, and women to hide, this girl set forth. Essence of womanhood impregnates color and mass" (Hogrefe 108).

The sexual interpretations of O’Keeffe’s work, however, obscure her other influences, such as Kandinsky’s Concerning the Spiritual in Art. Indeed, O’Keeffe’s made frequent references to Kandinsky’s writings and works, which emphasized spiritual metaphors. Her paintings portrayed a mystical world, one that was close to her own psyche. In fact, after every gallery opening, she felt sickened because her art was so important to her that she felt personally invaded by the people who frequented gallery openings. Even the prospect of selling and parting with her work was difficult to grasp, and often she attempted to buy some of it back.

After Stieglit’s first wife divorced him in 1924, O’Keeffe reluctantly agreed to marry him. Although she did not feel the need to get married, he insisted on it. However, O’Keeffe kept her own name, and their life as a married couple was far from conventional. At this time, she began to paint large flowers, inspired by Paul Strand’s precisionist photography and from her early memories of flowers in high school art class. Although O’Keeffe credited the nineteenth century painter Henri Fantin-Latour as her influence in this regard, her treatment of flowers was unique, making her own portfolio particularly distinct. Stieglitz first comments upon seeing Georgia’s flowers were negative, which made her very upset. Many critics viewed the flower paintings as sexually charged, as the blossoms depicted were themselves the reproductive organs for plants. Others, however, referred more generally to the spiritual qualities of the paintings. Glenn Mullin stated: "We intuitively feel and recognize the truth she has made Of the essence of things" (Hogrefe 131).

O’Keeffe produced a proportion of her most popular work that was exhibited in 1925. These paintings sold for astronomical prices, ensuring her financial success. Following the success of her flowers, in 1925 she began to paint the city. In 1927, she underwent an operation to remove a benign tumor in her breast. Her experience, specifically her last moments of consciousness, induced her to paint Black Abstraction, which featured highly inventive geometrics. O’Keeffe and Stieglitz spent their summers at the Stieglitz family house at Lake George, where Georgia started to paint her nature abstractions.

After the winter of 1929, Georgia felt the need to leave New York. Her painting had become such an important part of her life that she suffered when she lacked the creative impulses that sustained her. Even a doctor recommended a change, and she made the difficult decision to leave Stieglitz for that summer and travel to New Mexico. O’Keeffe’s friend, Beck Strand, Paul Strand’s wife, accompanied her to Taos and Santa Fe. Taos had become a noted artists’ colony during the early twentieth century, inhabited by people such as Maurice Stern, D. H. Lawrence, and Mabel Dodge Luhan. O’Keeffe, enthralled by the landscape of New Mexico, returned to New York only because of Stieglitz.