Nicknamed "The Ol' Redhead", he was primarily identified with broadcasts of Major League Baseball, calling play-by-play across four decades with the Cincinnati Reds (1934–1938), Brooklyn Dodgers (1939–1953), and New York Yankees (1954–1966).

Like his fellow sportscasting pioneer Mel Allen, Barber also developed a niche calling college and professional American football in his primary market of New York City.

After four more years at WRUF he landed a job broadcasting the Cincinnati Reds on WLW and WSAI when Powel Crosley Jr. purchased the team in 1934.

On Opening Day 1934 (April 17), Barber attended his first major league game and broadcast its play-by-play, as the Reds lost to the Chicago Cubs 6–0.

In 1946, he added to his Brooklyn duties a job as sports director of the CBS Radio Network, succeeding Ted Husing and continuing through 1955.

There, his greatest contribution was to conceive and host the CBS Football Roundup, which switched listeners back and forth between broadcasts of different regional college games each week.

Barber called Dodgers broadcasts over New York radio station WHN (later WMGM) at 1050 on the AM dial, teaming with Al Helfer from 1939 to 1941, followed by Alan Hale in 1942 and Connie Desmond beginning in 1943.

When he developed a severe bleeding ulcer in 1948 and had to take a leave of absence from broadcasting for several weeks, Dodgers president Branch Rickey arranged for Ernie Harwell, the announcer for the minor-league Atlanta Crackers, to be sent to Brooklyn as Barber's substitute; in exchange, Cliff Dapper, the catcher for the Dodgers' farm team in Montreal, was permitted to go to Atlanta to serve as the Crackers' new player-manager, thereby effecting the first player-for-announcer "trade" in major league history.

He recruited the Fordham University graduate Vin Scully for CBS football coverage, and eventually invited him into the Dodgers' broadcast booth to succeed Harwell in 1950 after the latter's departure for the crosstown New York Giants.

That same year, the Dodgers began airing regular television broadcasts over WOR-TV, Channel 9 in New York, with the trio of Barber, Desmond, and Scully now alternating play-by-play for the team's games on both radio and TV.

Barber was the first person outside the team's board of directors to be told by Branch Rickey that the Dodgers had begun the process of racial desegregation in baseball, which led to signing Jackie Robinson as the first black player in the major leagues after the 1880s.

As a Southerner, having lived with racial segregation as a fact of life written into law, Barber told Rickey that he was not sure he could broadcast the games.

During this period, Barber also broadcast numerous World Series for Mutual radio and in 1948 and 1952 for NBC television, frequently teaming with Yankees announcer Mel Allen.

With the Yankees, Barber strove to adopt a strictly neutral, dispassionately reportorial broadcast style, avoiding not only partisanship but also any emotional surges that would match the excitement of the fans.

He authored a number of books, including his autobiography, Rhubarb in the Catbird Seat; contributed to occasional sports documentary programs on radio and television, including Ken Burns' documentary Baseball; and from 1981 until his death made weekly contributions to National Public Radio's Morning Edition program.

[8] Edwards' book Fridays with Red: A Radio Friendship[9] based on his Morning Edition segments with Barber, was published in 1993.

In 1978, Barber joined former colleague Mel Allen to become the first broadcasters to receive the Ford C. Frick Award from the National Baseball Hall of Fame and Museum.

The Red Barber Radio Scholarship is awarded each year by the University of Florida's College of Journalism and Communications to a student studying sports broadcasting.

In the 2013 film 42, which dramatizes Jackie Robinson breaking the major leagues' color barrier with the Dodgers, Barber is played by John C. McGinley.