Grimes was born in Emerald, Wisconsin. He was the first child of Nick Grimes, a farmer and former day laborer, and the former Ruth Tuttle, the daughter of a former Wisconsin legislator. Having previously played baseball for several local teams, Nick Grimes managed the Clear Lake Yellow Jackets and taught his son how to play the game early in life. Burleigh Grimes also participated in boxing as a child.
Grimes played for the Pittsburgh Pirates in 1916 and 1917. Before the 1918 season, he was sent to the Brooklyn Dodgers in a multiplayer trade. When the spitball was banned in 1920, he was named as one of the 17 established pitchers who were allowed to continue to throw the pitch. According to Baseball Digest, the Phillies were able to hit him because they knew when he was throwing the spitter. The Dodgers were mystified about this; first they thought the relative newcomer of a catcher, Hank DeBerry, was unwittingly giving away his signals to the pitcher, so they substituted veteran Zack Taylor, to no avail. They suggested that a spy with binoculars was concealed in the scoreboard in old Baker Bowl in Philadelphia, reading the signals from a distance, but the Phils hit Grimes just as well in Ebbets Field in Brooklyn. A batboy solved the mystery by pointing out that Burleigh's cap was too tight. It sounded silly, but he was right. The tighter cap would wiggle when Grimes flexed his facial muscles to prepare the spitter. He got a cap a half-size larger and the Phillies were on their own after that.
At the time of his retirement, he was the last of the 17 spitballers left in the league. He had acquired a lasting field reputation for his temperament. He is listed in the Baseball Hall of Shame series for having thrown a ball at the batter in the on-deck circle. His friends and supporters note that he was consistently a kind man when off the diamond. Others claim he showed a greedy attitude to many people who 'got on his bad side.' He would speak mainly only to his best friend Ivy Olson in the dugout, and would pitch only to a man named Mathias Schroeder before games. Schroeder's identity was not well known among many Dodger players, as many say he was just 'a nice guy from the neighborhood.'
Grimes was the manager of the Dodgers in 1937-38. He followed Casey Stengel's term as Dodgers manager. He compiled a two-year record of 131-171 (.434), with his teams finishing sixth and seventh respectively in the National League. Babe Ruth was one of Grimes's coaches. Leo Durocher was the team's shortstop in 1937 and a coach in 1938. When Grimes was fired by general manager Larry MacPhail after the 1938 season, Durocher was hired to replace him. MacPhail said that the team's morale had not been right for a long period of time.