Nixon attended the University of Michigan, graduating in 1969 with a degree in English. He went on to earn an M.F.A. from the University of New Mexico in 1974.

His first exhibition was at the Museum of Modern Art under curator John Szarkowski in 1976. His early work was claimed as part of the New Topographics which kicked off at the International Museum of Photography at George Eastman House. In 1976 Nixon was awarded a National Endowment for the Arts Photography Fellowship. In 1977 and 1986 he was awarded Guggenheim fellowships.

Influenced by the photographs of Edward Weston and Walker Evans, Nixon began working with large-format cameras. Whereas most professional photographers had abandoned these cameras in favor of shooting on 35 mm film with more portable cameras, Nixon prefers the format because it allows prints to be made directly from the 8x10 inch negatives, retaining the clarity and integrity of the image. Nixon has said "When photography went to the small camera and quick takes, it showed thinner and thinner slices of time, [unlike] early photography where time seemed non-changing. I like greater chunks, myself. Between 30 seconds and a thousandth of a second the difference is very large."

In 1975, Nixon began one of his most famous projects entitled The Brown Sisters. The series consists of one portrait per year of four sisters, one of whom is Nixon's wife, always posed in the same left to right order. As of 2010 he is still contributing to the series and there are thirty one portraits altogether. The series has met critical acclaim and has been shown at the Museum of Modern Art, Harvard University's Fogg Art Museum, and the Cincinnati Art Museum. Currently, the collection is being shown at the National Gallery of Art.

Nixon is also well known for his work People With AIDS which he began in 1987. Documenting the debilitation and devastation wreaked by the disease, People With AIDS was alternately heralded as compassionate and life-affirming and condemned by HIV/AIDS activists as cruel and exploitive. The activist group Act Up! picketed the opening exhibition of the collection because it showed only patients suffering and none which were, in the organization's words, "vibrant and sexy." The photographs were collected in a book of the same name with text from the subjects depicted.

Among other subjects featured in Nixon's photography are people in nursing homes, schoolchildren, the city of Boston, the blind, and documentation of home life with his wife Bebe, and two children, Samuel and Clementine Nixon.

Nixon has worked as a part-time professor at the Massachusetts College of Art and Design since 1975.