After graduation, he continued his studies in medicine at Yale University, which he completed in 1970, also graduating Magna Cum Laude. Later he specialized in general and pediatric surgery at Harvard University. Following his residency at Harvard, he practiced medicine in Puerto Rico while also attending the University of Puerto Rico, Medical Sciences Campus where he earned a master's degree in Public Health (MPH) in 1981 (also graduating Magna Cum Laude). In 2011, he began studying toward a Doctor of Education in Education Leadership from the University of Turabo, graduating in 2015. During his college years, Rosselló became an avid tennis player that led him to be named the captain of Notre Dame's Men's tennis team, a P.R. 5-time-Mens-Champion, and also to play for Puerto Rico's team in regional championships, including the Central American and Caribbean Games. He was inducted into the Puerto Rico Tennis Hall of Fame in 2004. Rosselló started his professional career alternating as an instructor at Harvard Medical School and as an assistant professor at the University of Puerto Rico, Medical Sciences Campus, where he would later become an associate professor. He became chief of pediatric surgery and later chief surgeon at the University of Puerto Rico Children's Hospital. In 1985, Rosselló was named Health Services Director for the city of San Juan by then Mayor Baltasar Corrada del Río. Rosselló began his political career in 1988 when he ran for the office of Resident Commissioner of Puerto Rico, (the island's non-voting observer/representative in the United States Congress) losing to incumbent Jaime Fuster of the Popular Democratic Party (PPD). Nevertheless, he was the candidate from the New Progressive Party (PNP) for whom the most votes were cast in the 1988 elections. This positioned him well to become the party's next leader. After leading a "Statehood Crusade" throughout the islands of Puerto Rico, in 1991 he became president of the PNP, successfully leading an opposition to a referendum sponsored by the then Puerto Rico's Governor Rafael Hernández Colón. In 1992 he successfully ran for Governor of Puerto Rico, defeating Victoria Muñoz Mendoza of the PPD. As governor, Rosselló launched an anti-crime campaign known as ""Mano Dura Contra el Crimen"" ("literally, "Strong hand against crime"") in which the Puerto Rico National Guard was used to assist state police in deterring the ever-increasing crime wave that had begun in the late 1980s.