Born Ramona Victoria Epifanía Rufina Ocampo in Buenos Aires into a high-class society family, she was educated at home by a French governess. She would later write, "the alphabet-book in which I learned to read was French, as was the hand that taught me to draw those first letters."

She is sometimes said to have attended the Sorbonne: on page 39 of her biography of VO, Doris Meyer states that, during the family's 1906-1907 trip to Paris, the same during which she was etched by Paul César Helleu, the Ocampos allowed 17-year-old Victoria, "well-chaperoned", to audit some lectures at the Sorbonne and at the Collège de France. She remembered particularly enjoying Henri Bergson's lectures at the latter. She was not, of course, ever matriculated at either; her very old, traditional and rich family frowned on formal education for females, and so Victoria had none.

In 1912 Ocampo married Bernando de Estrada (aka Monaco Estrada). The marriage was not happy, and in 1920, the couple separated, and Ocampo began a 13-year affair with her husband's cousin Julián Martínez, a diplomat.

In Buenos Aires, she was a lynchpin of the intellectual scene of the 1920s and '30s. Her first book, written in French, was De Francesca à Beatrice (1923?), a commentary on Dante's Divine Comedy; other works include Domingos en Hyde Park; El Hamlet de Laurence Olivier; Emily Brontë (Terra incógnita); a series called Testimonios (ten volumes); Virginia Woolf, Orlando y Cía; San Isidro; 338171 T.E. (Lawrence of Arabia) (a biography of T. E. Lawrence) and a posthumously published autobiography. There is also an edited book of dialogues between Ocampo and Borges.

Perhaps of greater significance than her own writing, she was founder (1931) and publisher of the magazine Sur, the most important literary magazine of its time in Latin America. Among the writers published in Sur were Jorge Luis Borges, Ernesto Sabato, Adolfo Bioy Casares, Julio Cortázar, José Ortega y Gasset, Manuel Peyrou, Albert Camus, Enrique Anderson Imbert, José Bianco, Santiago Davobe, Ezequiel Martínez Estrada, Pierre Drieu La Rochelle, Waldo Frank, Gabriela Mistral, Eduardo Mallea, Silvina Ocampo (her younger sister), Alfonso Reyes, María Luisa Bastos, Peregrina Pastorino, Nicolás Barrios Lynch and Enrique Pezzoni.

During World War II she supported and edited form Argentina, the anti-nazi magazine "Lettres Francaises" directed by Roger Caillois and in1946 she was the only Argentinean who attendet the Nuremberg Trials.

In 1953, Ocampo was briefly imprisoned for her open opposition to the regime of Juan Domingo Perón.

She was made a member of the Argentine Academy of Letters in 1976 (the first woman ever admitted to the Academy; she formally took her seat on June 23, 1977). The "cultural dialog", initiated in 1977 by the de facto government but organized by UNESCO, was held in her home, Villa Ocampo, in San Isidro, Buenos Aires Province; she eventually donated the house to UNESCO.

At "Villa Ocampo" Igor Stravinsky, André Malraux and Rabindranath Tagore had been her guests there, also Indira Gandhi,José Ortega y Gasset, Antoine de Saint-Exupéry, Ernest Ansermet, Rafael Alberti etc. Graham Greene dedicated his 1973 novel The Honorary Consul to her, "with love, and in memory of the many happy weeks I have passed at San Isidro and Mar del Plata" and in 1934 she was the recitant in the American premiere of André Gide-Igor Stravinsky's opera-ballet Perséphone at the Teatro Colón conducted by the composer.

Victoria Ocampo died in Buenos Aires in 1979, and is buried in La Recoleta Cemetery in Buenos Aires.