After being named the Carolina League's "Most Valuable Player" for 1962, Rusty Staub received a $100,000 bonus from the Astros (then named the Colt .45s) and debuted as a 19-year-old rookie in 1963. By 1967, when he led the league in doubles with 44, his compact left-handed stroke and line drive hitting ability had made him an all-star. He would also make All-Star teams in 1968-70 and 1976.

Traded to the Expos before the start of the 1969 season, he was embraced as the expansion team's first star and became one of the most popular players in that franchise's history. Embraced by French-Canadians because he made the effort to learn their language, he was nicknamed "Le Grande Orange" for his red hair (his more common nickname of "Rusty" has the same origin). Staub's #10 jersey (he later wore #6) was the first number ever retired by the Montreal Expos organization.

Moving on to the Mets in 1972, he was instrumental in the Mets' upset 1973 National League Championship Series victory when he robbed Dan Driessen of an extra-base hit in the 11th inning, though the resulting injury to his arm forced him to throw underhand in that year's World Series. In 1975, he set a Mets record with 105 RBIs that would stand until 1987.

After the 1975 campaign Rusty was traded to the Detroit Tigers for Mickey Lolich in a swap of superstars. In 3+ seasons with the Tigers, Rusty knocked in 358 runs, was voted to start the 1976 All-Star game.

In 1978, Staub became the first player to play in all 162 regular-season games exclusively as a designated hitter. Not playing the field at all proved beneficial as Staub finished second in the Major Leagues with 121 RBI. He was also named as the Designated Hitter on The Sporting News 1978 AL All-Star team.

Rusty held out to start the 1979 campaign and this resulted in him being dealt to the Montreal Expos in July of that same season. This would mark the end of Staub being an everyday player in the Major Leagues.

Staub returned to the Mets in 1981 as a free agent after spending the 1980 season with the Texas Rangers. In 1983 he tied a National League record with eight straight pinch-hits and that same season also tied the Major League record of 25 RBIs by a pinch hitter. Rusty Staub wrapped up his career with the Mets at the age of 41 in 1985. He retired as the only major league player to have 500 hits with four different teams, and he shares the distinction with Ty Cobb of being the only player to hit a home run before age 20 and after age 40.

Following his retirement from baseball in 1985, Staub opened a New Orleans-style restaurant in New York City and worked as an announcer for Mets ball games.

A humanitarian, he established the "Rusty Staub Foundation" to do charitable works and in 1986 founded the "New York Police and Fire Widows' and Children's Benefit Fund." During its first 15 years of existence, the Fund raised and distributed $11 million for families of policemen and firefighters killed in the line of duty. Since September 11, 2001, Staub's organization has received contributions in excess of $112 million and has played a vital role in helping many families affected by the tragedy.

Staub was inducted into the New York Mets Hall of Fame in 1986. In 2004, he received an honorary doctor of humane letters degree from Niagara University.