Born in New Orleans, Wilson graduated from Warren Easton High School and entered Tulane University’s School of Architecture in 1927 at the age of sixteen. He worked part-time for architect Moise Goldstein while attending college and was employed there full-time when he graduated in 1931. Wilson left in 1934 to work for the Historic American Buildings Survey (HABS) with architect Richard Koch, documenting such buildings as the Beauregard-Keyes House and the Old Ursuline Convent. He became an architect at Koch’s firm in 1935, where he worked on Works Progress Administration projects in New Orleans’ City Park. Having received an American Institute of Architects (AIA) scholarship in 1938, Wilson traveled to Europe to study the origins of Louisiana architecture. He served in the U.S. Coast Guard Reserve from 1942 to 1945, after which he returned to Koch’s office and became an adjunct professor at Tulane, where he lectured for 38 years. Wilson began a partnership with Koch in 1955 that ended when Koch passed away in 1971. Wilson’s two architectural firms, Richard Koch and Samuel Wilson, Jr., and its successor, Koch and Wilson Architects, rehabilitated many significant historic structures in Louisiana and Mississippi, including the Old Ursuline Convent, Shadows-on-the-Teche, Gallier House, Hermann-Grima House, Beauregard-Keyes House, French Market, Pitot House, and numerous others in the Vieux Carré alone.
Wilson helped establish the Louisiana Landmarks Society in 1949, serving as its first president from 1950 to 1956. He co-founded the Orleans Parish Landmarks Commission, Save Our Cemeteries, and the Preservation Resource Center, and served as the director of the Society of Architectural Historians. Wilson was elected an AIA Fellow in 1955, and was awarded the Louisiana Architects Association Medal of Honor in 1987, as well as an honorary PhD from Tulane. Wilson passed away in New Orleans at the age of 82.