Simmons holds appointments as a professor in the Departments of Comparative Literature and Africana Studies. In 2002, Newsweek selected her as a Ms. Woman of the Year, while in 2001, Time named her as America's best college president. She received her bachelor's degree from Dillard University in New Orleans in 1967 and received her master's and doctorate in Romance literature from Harvard University in 1970 and 1973 respectively. She was a professor of Romance languages and became a dean at Princeton University from 1983 to 1990, and then became the first African American woman to head a major college or university as president of Smith College from 1995 to 2001. She became president of Brown in 2001.
Simmons started the engineering program at Smith. At Brown, she has launched an ambitious $1.4 billion initiative known as the Campaign for Academic Enrichment in order to enhance Brown’s academic programs.
In a 2006 orientation meeting with parents, Simmons denied interest in the presidency of Harvard University, which at the time was headed by an interim president, Derek Bok. Nevertheless, a 2007 New York Times article, featuring a photograph of Simmons, reported that the Harvard Corporation, responsible for selecting the university's replacement for former president Lawrence Summers had been given a list of "potential candidates" that included her name.
Simmons also serves on the boards of Texas Instruments and Goldman Sachs. She announced in 2007 that she would not seek re-election to the board of directors of Pfizer after serving on the board for 10 years.