Weaver managed the Baltimore Orioles for 17 seasons (1968–86), leading them to four American League titles—three in succession, from 1969 to 1971—and the World Series championship in 1970. A second baseman during his playing career, Weaver never played in the major leagues but began managing in the minor leagues at age 25. Beginning in 1958, he managed all of Baltimore's minor league teams before becoming a coach with the Orioles in 1968. Weaver replaced Hank Bauer as manager during the 1968 season and reinvigorated the Baltimore organization. His Orioles teams won 100 or more games on five occasions, and he was twice named Manager of the Year (1977 and 1979). In 1982 Weaver retired and became a network television analyst; however, in 1985 he returned to manage the Orioles midway through the season and stayed on for 1986. That year, Weaver's team won 73 games and lost 89, his only losing campaign as a major league manager, and he resigned at the end of the season.

Weaver was an early user of computers to analyze data on opposing pitchers. He was also a very aggressive manager who seldom shied away from challenging umpires and was ejected from more than 90 games, making him the third-most ejected manager in baseball history. He was elected to the Baseball Hall of Fame in Cooperstown, N.Y., in 1996.