First elected Mayor of Charleston, South Carolina in December 1975, Riley served for over ten terms. Riley was the city's longest serving executive and second Irish Catholic mayor.

Riley's first major project was pushing the redevelopment of the central business district. City Council approved $12,500 for a feasibility study for a redevelopment plan on June 7, 1977. A Washington, D.C. consulting group recommended that the city should build a large hotel, commercial, and conference center, and the largely vacant 5-acre lot bounded by King, Meeting, Hasell, and Market streets was a prime candidate. In mid-1977, developer Theodore Gould made a proposal for a $40 million project to be known as the "Charleston Center." The conceptual plans called for a 14-story building with a 700-car parking garage, and preservationists came out strongly against the plans. On January 25, 1978, the first of several lawsuits was filed in an effort to scale back the massive size of the project. Work began in 1981 after several legal challenges. On May 16, 1983, revised plans were released showing the building as it would eventually appear: eight stories in the center but only four around the perimeter. When Gould was unable to secure financing, the city replaced him with new backers and renamed the project "Charleston Place." The center opened on September 2, 1986. Its final cost was approximately $75 million.

Riley supported another project meant to spur redevelopment in 1987 with a proposal to build a visitor center on upper Meeting Street.

Riley has pursued several projects involving public access to the city's waterfront. In 1987, he announced a deal that he had secretly negotiated with a property owner to purchase 5.53 acres of waterfront property along the Cooper River near the present site of the South Carolina Aquarium. The agreement resulted in the city's paying $2.5 million for the land worth between $3.3 and $3.75 million. In 1989, Riley served on the selection committee for the Rudy Bruner Award for Urban Excellence.

Riley ran for Governor of South Carolina in 1994, finishing second in the Democratic primary behind Lieutenant Governor Nick Theodore.

Riley is a member of the Mayors Against Illegal Guns Coalition, a bi-partisan group with a stated goal of "making the public safer by getting illegal guns off the streets." The Coalition was co-founded by former Boston Mayor Thomas Menino and former New York City Mayor Michael Bloomberg.

Riley served as President of the U.S. Conference of Mayors for 1986–1987. He served on the USCM Executive Committee. He is a founder of the Mayors' Institute on City Design.

Riley is on the Board of Selectors of Jefferson Awards for Public Service.

Riley was elected to his seventh term on November 2, 1999 with 71% of the vote; city councilman Maurice Washington received 29%.

When the Confederate battle flag was flown above the South Carolina statehouse, Riley organized a five-day protest walk from Charleston to Columbia to promote its removal. The march began on April 2, 2000, with about 600 marchers; the crowd dropped dramatically during the week but rebounded to about 400 marchers before a protest held on the statehouse grounds on April 6, 2000.

Riley won his eighth term as mayor in November 2003 in the city's first nonpartisan election with 57% of the vote against other candidates including Jimmy Bailey (32%) and Kwadjo Campbell (9%).

Following a Sofa Super Store fire, which killed nine Charleston firemen, Riley proposed the city's purchase of the location of the fire and its development as a passive park.

Riley's legacy project, that he describes as the most important thing he's done as mayor, is the International African American Museum. Located on the former Gadsden's Wharf - the site where over 40% of all enslaved Africans brought to this country took their first steps, the museum is a $75MM project with world-class partners Ralph Applebaum & Associates and Pei Cobb Freed. It is scheduled to open in 2018.

After his service as mayor, Riley returned to The Citadel as a professor of American Government and Public Policy, a position which has been endowed and named for him.