Two years after Ross was born, his family moved to Chicago's Maxwell Street ghetto, where they opened a small grocery. Misfortune soon struck the family, however. By the time Ross was age 14, his father had been murdered by gangsters, his mother had suffered a nervous breakdown, and his younger siblings had been placed in an orphanage. Ross dropped out of school and became a petty thief, an errand boy for mobster Al Capone (Capone, Al), a street fighter, and eventually an amateur boxer. After winning a Golden Gloves amateur championship in 1929, Ross began his professional boxing career. He won a 10-round decision (a fight whose outcome is determined by judges' scoring) over American Tony Canzoneri (Canzoneri, Tony) on June 23, 1933, to gain simultaneously the world lightweight and junior welterweight (also known as super lightweight) titles. On Sept. 18, 1933, Ross won a 15-round decision in a rematch with Canzoneri for both titles. Following three more successful defenses of his junior welterweight title, Ross moved up to the welterweight division and won the world championship by decision over Irish-born Canadian Jimmy McLarnin in 15 rounds on May 28, 1934, but he lost the title back to McLarnin in a 15-round decision on Sept. 17, 1934. Following three more successful defenses of his junior welterweight title, Ross relinquished it in order to fight McLarnin again for the welterweight title, which he won with a 15-round decision on May 28, 1935. Ross defended it by winning 15-round decisions over American Izzy Jannazzo on Nov. 27, 1936, and Filipino Ceferino Garcia on Sept. 23, 1937. Ross lost the title in a 15-round decision to the reigning featherweight (126 pounds) champion, Henry Armstrong (Armstrong, Henry) of the United States, on May 31, 1938. It was the final fight in an 81-bout professional career in which Ross compiled a record of 72 wins (22 by knockouts), 4 losses (all by decision), 3 draws, and 2 no decisions.

Ross joined the U.S. Marine Corps in 1942, and he was awarded a Silver Star for “conspicuous gallantry and intrepidity in action” for his heroics at the Battle of Guadalcanal (Guadalcanal, Battle of) (August 1942–February 1943), where he was wounded. His autobiography, No Man Stands Alone: The True Story of Barney Ross (1957), includes a chapter on his struggles with an addiction to morphine that began during his medical treatment on Guadalcanal. His life is depicted in the motion picture Monkey on My Back (1957).

Ross was one of the greatest Jewish fighters of the 1930s, a period in which Jews were at the forefront of the boxing world. His battles with the Italian American Canzoneri and the Irish Canadian McLarnin revitalized public interest in the sport. Ross was inducted into the International Boxing Hall of Fame in 1990.