Born in Toledo, Ohio, he began his major league career as a pitcher, throwing a six-hit shutout on August 27, 1897. However, he eventually moved to catcher (although he could play all nine positions), and was labeled one of the best at that position by managers John McGraw and Branch Rickey. Despite taunts by other players, he experimented with head and thigh protection gear which had been introduced by some college teams, and this led to the widespread use of more protection for catchers in the early 20th century. He played for the Washington Senators (1897), Chicago Orphans/Cubs (1900, 1913-15), Baltimore Orioles (1901-02), New York Giants (1902-08), St. Louis Cardinals (1909-12), and the Cubs again (1913-1915). In 1430 games, he had a batting average of .279 in 4480 at-bats.

In 1911, with the Cards only three games out of first place in early July, the team was involved in a train wreck on its way from Philadelphia to Boston. 47 passengers were injured, while twelve died. None of the Cardinals were seriously injured, due to a pre-trip change in the location of their car to the rear of the train. Cards star Ed Konetchy and Bresnahan led the rescue effort, carrying many passengers to safety, some of whom may have died. Despite posting their first winning season since 1901, the Cardinals never recovered from the incident, finishing a distant fifth.

Bresnahan had managed the Cardinals while playing for them, and the Cubs in 1915. His overall record was 328-432.

Bresnahan died of a heart attack at his home in Toledo at age 65, and was elected to the Hall of Fame the following year.

His Hall of Fame plaque says the following:

ROGER BRESNAHAN BATTERY MATE OF CHRISTY MATHEWSON WITH THE NEW YORK GIANTS, HE WAS ONE OF THE GAME'S MOST NATURAL PLAYERS AND MIGHT HAVE STARRED AT ANY POSITION. THE "DUKE OF TRALEE" WAS ONE OF THE FEW MAJOR LEAGUE CATCHERS FAST ENOUGH TO BE USED AS A LEADOFF MAN.