She earned her bachelor’s degree, on scholarship, from Dillard University in New Orleans, Louisiana, in 1967. She went on to earn her master’s and doctorate in Romance literature from Harvard University in 1970 and 1973, respectively.

Simmons was an assistant professor of French at the University of New Orleans from 1973-1976 and Assistant Dean of the UNO College of Liberal Arts from 1975–76. She moved to California State University, Northridge in 1977 as administrative coordinator of its NEH Liberal Studies Project. From 1978–79, she was acting director of CSU-Northridge’s International Programs and visiting associate professor of Pan-African Studies.

Simmons moved to the University of Southern California in 1979 as assistant dean of graduate studies, and then as associate dean of graduate studies. She moved to Princeton University in 1983 and served as assistant dean of faculty and then associate dean of faculty from 1986 to 1990. Simmons served as provost at Spelman College from 1990 to 1991 and returned to Princeton as its vice provost from 1992 to 1995.

In 1995 Simmons became the first African-American woman to head a major college or university when she was selected as president of Smith College, which she led until 2001. As president of Smith College, Simmons started the first engineering program in a U.S. woman’s college.

Simmons became president of Brown in October 2001, succeeding Gordon Gee. At Brown, she completed a $1.4 billion initiative – the largest in Brown’s history – known as Boldly Brown: The Campaign for Academic Enrichment in order to enhance Brown’s academic programs. In 2004, former Brown student Sidney E. Frank made the largest aggregate monetary contribution to Brown in its history in the amount of $120 million. The Frank gifts were principally devoted to scholarship assistance to Brown students and to Brown’s programs in the sciences.

As the wealth that the founding Brown family contributed to the university was based in part on the triangular slave trade, in 2003, Simmons established the University Steering Committee on Slavery and Justice to examine this complex history and make recommendations for how the university might approach the relevant issues. The Report of the Brown University Steering Committee on Slavery and Justice was subsequently published. On February 16, 2007, at an event celebrating the 200-year anniversary of the passage of the Slave Trade Act of 1807 and the involvement of Cambridge University alumni William Wilberforce, Thomas Clarkson and William Pitt the Younger, Simmons delivered a lecture at St. John’s College, Cambridge, entitled Hidden in Plain Sight: Slavery and Justice in Rhode Island. Also in February 2007, Brown University published its official Response to the Report of the Steering Committee on Slavery and Justice following completion of the historic inquiry undertaken by the committee appointed by Simmons. The bicentenary of the British abolition of the slave trade was also commemorated at Oxford University, notably at Rhodes House.

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.

By early 2007, philanthropist Warren Alpert made a similarly generous contribution to strengthen the programs of The Warren Alpert Medical School of Brown University in the amount of $100 million, matching the core portion of the Sidney Frank gift to Brown. As reported in a May 22, 2009, press release, Brown chancellor Thomas J. Tisch announced early accomplishment of the $1.4 billion fundraising campaign and the continued pursuit of specific subsidiary goals in support of endowments for student scholarships, the Brown faculty and internationalization programs through the originally planned campaign completion date of December 31, 2010.

In August 2007, Simmons was invited to deliver the 60th Annual Reading of the historic 1790 George Washington Letter to Touro Synagogue at the Synagogue in Newport, Rhode Island in response to Moses Seixas on the subject of religious pluralism.

In October 2007, Simmons appointed David W. Kennedy, the former Manley O. Hudson Professor of Law at Harvard Law School, as vice president for international affairs. In addition to supporting the leadership of the Watson Institute for International Studies, the new university officer will lead a multidisciplinary advanced research project in the field of global law, governance and social thought to strengthen the University’s international work in the social sciences.

Simmons also serves on the boards of Texas Instruments and Fiat Chrysler Automobiles. 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.

As an additional element of Simmons’ leadership of Brown’s international efforts, Brown and Banco Santander of Spain inaugurated an annual series of International Advanced Research Institutes to convene a rising generation of scholars from emerging and developing countries at Brown in a signing ceremony on November 13, 2008, at the John Hay Library between Brown provost David Kertzer and Emilio Botin, chairman of Banco Santander. As noted by Simmons: “To be at the forefront of research today means being in conversation with global peers. The Brown Institutes provide exciting opportunities to encounter new ideas, build collegiate relationships and enrich faculty development for young scholars and teachers from around the world”.

Simmons earned annual compensation of over $300,000 from Goldman Sachs (on top of her annual salary from Brown of over $500,000) while serving on the Goldman board of directors during the late-2000s financial crisis; in addition, she left the Goldman board (which she had joined in 2000) in 2009 with over $4.3 million in Goldman stock. During her term on Goldman’s board, she also served on the compensation committee of Goldman’s ten-person board, which decided how large Goldman executives’ post-crash bonuses would be; these bonuses included a $68 million bonus for the company’s chairman and CEO, Lloyd C. Blankfein, in 2007 and a $9 million bonus in 2009 after Goldman received money in the federal TARP bailout. The revelations of Simmons’s role received intense criticism from both alumni and students, with a then-sophomore stating that Simmons’s actions “brought shame on the university.” Simmons was cited in the 2010 film Inside Job, as an example of the conflicts of interest between university economics departments and deregulation of financial institutions.

On June 17, 2009, The White House announced that President Barack Obama had appointed Dr. Simmons to the President’s Commission on White House Fellowships. In February 2010, Simmons received a BET Honors award for her service as president of Brown University. In 2010, she was awarded the Ellis Island Medal of Honor for her many humanitarian efforts.

In March 2010, Simmons traveled to India as part of a major program called the Year of India which is dedicated to the improvement of understanding of Indian history, politics, education and culture among Brown students and faculty.

In September 2011, Simmons announced that she would step down from her position as Brown President at the end of the 2011–12 academic year, originally saying she would remain at Brown as a professor of comparative literature and Africana studies. She was succeeded as Brown President on June 30, 2012, by Christina Paxson.