His most prestigious contribution to the sport was early support of the first black Major League Baseball player, Jackie Robinson. He refused to sign a petition that threatened a boycott if Robinson joined the team. When Robinson joined the Dodgers in 1947 and traveled with them during their first road trip, he was heckled by fans in Cincinnati, Ohio. Reese, the captain of the team, went over to Robinson and put his arm around his shoulder in a gesture of support which silenced the crowd. The gesture was especially telling because Reese was born and raised in then-segregated Louisville, Kentucky.

Throughout that difficult first year in the major leagues, Reese helped keep Robinson's morale up amid all the abuse. Their rapport soon led shortstop Reese and second baseman Robinson to become one of the most effective defensive pairs in the sport's history.

At Reese's funeral, Joe Black, another Major League Baseball black pioneer, said:

"Pee Wee helped make my boyhood dream come true to play in the Majors, the World Series. When Pee Wee reached out to Jackie, all of us in the Negro League smiled and said it was the first time that a White guy had accepted us. When I finally got up to Brooklyn, I went to Pee Wee and said, 'Black people love you. When you touched Jackie, you touched all of us.' With Pee Wee, it was No. 1 on his uniform and No. 1 in our hearts."

In 1984, Pee Wee Reese was inducted into the Baseball Hall of Fame.

Following his retirement as a player, Reese enjoyed considerable success as a play-by-play announcer on network television. He called games for CBS from 1960-1965 (with Dizzy Dean) and for NBC from 1966-1968 (with Curt Gowdy). Reese also broadcast several World Series for NBC radio.

In front of the main entrance into Louisville Slugger Field, stands a statue of Pee Wee Reese.

The friendship between Reese and Robinson is the subject of a popular 1990 children's book called Teammates (ISBN 0152842853), by Peter Golenbock.