After studying at the Sorbonne in Paris, Sontag taught at Columbia University, New York City from 1960-64. She now began to contribute numerous essays to New York journals, especially Partisan Review, and rapidly became known for her ability to re-interpret in contemporary American terms an encyclopedic knowledge of ancient and modern European culture. One of her most influential insights came in an essay reprinted in her first collection, Against Interpretation and Other Essays (1968), where she argued for "transparency". An understanding of art, she wrote, began from an intuitive response and not from analysis or intellectual considerations.

In her second collection of essays, Styles of Radical Will (1969), Sontag wrote on drugs, pornographic literature, cinema and modern art and music. In her essay On Photography (1977), she famously declared that photography transformed people into "tourists of reality," thus further developing her concept of "transparency". Later volumes of essays include Illness and Metaphor (1978), written after treatment for cancer. Illness, she argued, is often seen in a punitive light, as a metaphor, rather than for what it is. The book was later revised and expanded as AIDS and its Metaphors (1988).

Sontag's political position has been equally radical, with fierce denunciations of the American action against Cuba and involvement in Vietnam. Consistently radical in outlook, she did not necessarily support orthodox left-wing poltics, and in fact declared in 1982 that "Communism is fascism". In 1993, she went to Sarajevo at the height of the city's siege by Serbian forces and directed a production of Samuel Beckett's Waiting for Godot.

Sontag is also the author of several novels, including The Benefactor (1963), a heavily symbolic work, and Death Kit (1967), a meditation on dream and reality. Her third book, The Volcano Lover (1992), is more accessible and became a bestseller. Set in the late 18th century, it tells the story of the triangular relationship between the British ambassador, Sir William Hamilton, his young wife Emma Hamilton and the naval hero, Lord Nelson. In 1999, she published In America, another novel based on historical events. It describes the attempt of a group of Polish immigrants to found a commune in California in the late 19th century.