In 1953, Bobby Mattick, a scout for the Cincinnati Reds, signed Robinson to a contract worth $3,500 ($33,446 in current dollar terms). He made his professional debut for the Ogden Reds of the Class C Pioneer League. He batted .348 with 83 runs batted in (RBI) in 72 games played. He was promoted to the Tulsa Oilers of the Class AA Texas League in 1954, but was demoted to the Columbia Reds of the Class A South Atlantic League. He returned to Columbia in 1955.

Robinson made his major league debut in 1956. In his rookie year with the Reds, Robinson tied the then-record of 38 home runs by a rookie and was named Rookie of the Year. The Reds won the NL pennant in 1961, and Robinson won his first MVP (in July he batted .409, hit 13 home runs, and drove in 34 runs to win NL Player of the Month), the last time the NL played a 154-game schedule. The Reds lost the 1961 World Series to the New York Yankees. In 1962, Robinson hit a career-high .342 with 39 home runs, 51 doubles, and 136 RBIs.

Robinson was noted as a fierce player. He spiked Johnny Logan in 1957, causing Logan to miss six weeks. He also got into a fistfight with Eddie Mathews in 1960.

Robinson met his wife, Barbara Ann Cole, in 1961. They married that year and lived in Los Angeles where Barbara sold real estate. They had two children. In 2003, he guest starred on an episode of Yes, Dear as himself, along with Ernie Banks and Johnny Bench.

Prior to the 1966 season, Reds owner Bill DeWitt traded Robinson to the Baltimore Orioles in exchange for pitcher Milt Pappas, pitcher Jack Baldschun and outfielder Dick Simpson. The trade turned out to be very lopsided. DeWitt, who had a slew of successful trades including his time as GM in Detroit and in the early 1960s rebuilding the Reds, famously referred to Robinson as “not a young 30” after the trade. The Reds led the NL in offense in 1965 and needed pitching. Pappas, who was a consistent performer in Baltimore was a major disappointment in Cincinnati while Robinson had continued success in Baltimore. In Robinson’s first year in Baltimore, he won the Triple Crown, leading the American League with a .316 batting average (the lowest ever by a Triple Crown winner), 49 home runs (the most ever by a right-handed Triple crown winner) and 122 runs batted in. On May 8, 1966, Robinson became the only player ever to hit a home run completely out of Memorial Stadium. The shot came off of Luis Tiant in the second game of a doubleheader against the Cleveland Indians, and the home run measured 541 feet (165 m). Until the Orioles’ move to Camden Yards in 1992, a flag labeled “HERE” was flown at the spot where the ball left the stadium.

In addition to his two Most Valuable Player awards (1961 and 1966) and his World Series Most Valuable Player award (1966), Robinson was honored in 1966 with the Hickok Belt as the top professional athlete of the year in any sport.

On June 26, 1970, Robinson hit back-to-back grand slams in the fifth and sixth innings in the Orioles’ 12–2 victory over the Washington Senators. The same runners were on base both times: Dave McNally was on third base, Don Buford was on second, and Paul Blair was on first.

On December 2, 1971, the Orioles traded Robinson and Pete Richert to the Los Angeles Dodgers for Doyle Alexander, Bob O’Brien, Sergio Robles and Royle Stillman. The 1972 season was his first season in the National League since playing with the 1965 Reds. He played 103 games, while compiling a .251 batting average, 59 RBIs, 86 hits, and 19 home runs.

He was traded along with Bill Singer, Bobby Valentine, Billy Grabarkewitz and Mike Strahler to the California Angels for Andy Messersmith and Ken McMullen at the Winter Meetings on November 28, 1972. The transaction was the result of Robinson’s request for regular playing time, something Dodgers general manager Al Campanis wanted for the team’s younger prospects. It also reunited him with Angels general manager Harry Dalton who had worked in a similar capacity when both were with the Orioles. In his time with the Angels, he became their first designated hitter while also being teammates again with Vada Pinson. He played 147 games in 1973 and 129 in 1974. In his tenure with the Angels, he hit for a .259 average while having 50 home runs, 249 hits, and 160 RBIs.

On September 12, 1974, the Angels traded Robinson to the Cleveland Indians for Ken Suarez, cash and a player to be named later (Rusty Torres). Three weeks later the Indians named him their manager and persuaded him to continue playing. In his first at bat as a player/manager for Cleveland in 1975, he hit a home run off of Doc Medich of the Yankees. He injured his shoulder in 1975 and did not play often. He retired from playing after the 1976 season, after batting .226 with 14 home runs in 235 at bats for Cleveland from 1974 through 1976.

Robinson managed in the winter leagues late in his playing career. By the early 1970s, he had his heart set on becoming the first black manager in the majors; the Angels traded him to the Cleveland Indians midway through the 1974 season due to his open campaigning for the manager’s job. In 1975, the Indians named him player-manager giving him the distinction of being the first black manager in the Majors. The Indians had a 79–80 record, and had an 81–78 record in 1976. Cleveland started the 1977 season 26–31, and fired Robinson on June 19, 1977.

In 1982, Robinson was inducted into the National Baseball Hall of Fame as a Baltimore Oriole. Robinson is also a charter member of the Baltimore Orioles Hall of Fame (along with Brooks Robinson), and a member of the Cincinnati Reds Hall of Fame, being inducted into both in 1978. He was named to the Washington Nationals Ring of Honor for his “significant contribution to the game of baseball in Washington, D.C” on May 9, 2015. He was inducted into the Cleveland Indians Hall of Fame in 2016. The Reds, Orioles, and Indians have retired his uniform number 20. He is one of only two major league players, the other being Nolan Ryan, to have his number retired by three different organizations.

Robinson managed the San Francisco Giants from 1981 through 106 games of the 1984 season, when he was fired. He finished the 1984 season as the hitting coach for the Milwaukee Brewers on a contract worth $1. In 1985, he joined the Orioles front office. He was named the manager of the Orioles for 1988. He was awarded the American League Manager of the Year Award in 1989 for leading the Orioles to an 87–75 record, a turnaround from their previous season in which they went 54–107.

In 1999, Robinson ranked 22nd on The Sporting News list of the 100 Greatest Baseball Players. He was nominated as a finalist for the Major League Baseball All-Century Team.

Robinson managed the Orioles through 1991, and the Montreal Expos/Washington Nationals franchise from 2002 through 2006. After Robinson had spent some years known in baseball as the Director of Discipline, he was chosen by Major League Baseball in 2002 to manage the Expos, which MLB owned at that time. The Expos, who had losing records in the five previous seasons, finished the 2002 and 2003 seasons with 83–79 records. The Expos then next slumped to a 67–95 record in 2004, their final season before relocation to Washington, D.C.

President George W. Bush awarded Robinson the Presidential Medal of Freedom on November 9, 2005. On April 13, 2007, Robinson was awarded the first Jackie Robinson Society Community Recognition Award at George Washington University.

On April 20, 2006, with the Nationals’ 10–4 victory over the Philadelphia Phillies, Robinson got his 1000th win, becoming the 53rd manager to reach that milestone. He had earned his 1000th loss two seasons earlier.

During a game against the Houston Astros on May 25, 2006, Robinson pulled Nationals catcher Matt LeCroy during the middle of the seventh inning, violating an unwritten rule that managers do not remove position players in the middle of an inning. Instead, managers are supposed to discreetly switch position players in between innings. However, LeCroy, the third-string catcher, had allowed Houston Astros baserunners to steal seven bases over seven innings and had committed two throwing errors. Although the Nationals won the game 8–5, Robinson found the decision so difficult to make on a player he respected so much, he broke down crying during post-game interviews.

On September 30, 2006, the Nationals’ management declined to renew Robinson’s contract for the 2007 season, though they stated he was welcome to come to spring training in an unspecified role. Robinson, who wanted either a front office job or a consultancy, declined. On October 1, 2006, he managed his final game, a 6–2 loss to the Mets, and prior to the game addressed the fans at RFK Stadium. Robinson’s record as a manager stood at 1,065 wins and 1,176 losses.

Robinson served as an analyst for ESPN during spring training in 2007. The Nationals offered to honor Robinson during a May 20 game against his former club the Baltimore Orioles but he refused.

In 2007 Robinson rejoined the MLB front office serving as a Special Advisor for Baseball Operations from 2007 to 2009. He then served as Special Assistant to Bud Selig from 2009 to 2010 and was named Senior Vice President for Major League Operations from 2010 to 2011. In June 2012, he became Executive Vice President of Baseball Development. In February 2015, Robinson left his position as Executive Vice President of Baseball Development and was named senior advisor to the Commissioner of Baseball and Honorary American League President.

On February 7, 2019, Robinson died of bone cancer in Los Angeles at the age of 83.