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 35mm film with more portable cameras, Nixon preferred the format because it allowed 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."
His first solo exhibition was at the Museum of Modern Art curated by John Szarkowski in 1976. Nixon’s early city views taken of Boston and New York in the mid-seventies were exhibited at one of the most influential exhibitions of the decade, New Topographics: Photographs of a Man-Altered Landscape at the George Eastman House in 1975. In the late nineties, Nixon returned to this subject matter to document Boston’s changing urban landscape during the Big Dig highway development project. In 1976, 1980, and 1987, Nixon was awarded National Endowment for the Arts Photography Fellowships. In 1977 and 1986, he was awarded Guggenheim fellowships.
Nicholas Nixon's subjects include schoolchildren and schools in and around Boston, people living along the Charles River near Boston and Cambridge as well as cities in the South, his family and himself, people in nursing homes, the blind, sick and dying people, and the intimacy of couples. Nixon is also well known for his work People With AIDS, begun in 1987.
In 1975, Nixon began his project, The Brown Sisters consisting of a single portrait of his wife, Bebe, and her three sisters each year, consistently posed in the same left to right order. As of 2012, there are thirty-eight portraits altogether. The series has been shown at the Museum of Modern Art, Harvard University's Fogg Art Museum, the Cincinnati Art Museum, the Modern Art Museum of Fort Worth and the National Gallery of Art. In 2010, the Museum of Fine Arts, Boston organized the exhibition "Nicholas Nixon: Family Album" which included "The Brown Sisters" series among other portraits of his wife Bebe, himself and his children Sam and Clementine.
- Photographs From One Year (1983)
- Pictures of People (1988)
- People With AIDS (with Bebe Nixon)(1991)
- School (1998)
- The Brown Sisters (2002)
- Nicholas Nixon Photographs (2003)
- Home (2005)
- Live Love Look Last (2009)
- Durrell, Jane (2005-04-06). "Photographer Nicholas Nixon pays attention to form". Retrieved 2007-07-11.