Nicknamed "Ol' Stubblebeard", Grimes was born in Emerald, Wisconsin. He made his professional debut in 1912 for the Eau Claire Commissioners of the Minnesota-Wisconsin League. He played in Ottumwa, Iowa, in 1913 for the Ottumwa Packers in the Central Association. He made his major league debut on September 10, 1916, for the Pittsburgh Pirates, and in 1920, when the spitball was banned, he was named as one of the 17 established pitchers who would be allowed to continue to throw the pitch. The 26-year-old Grimes made the most of this advantage, and over the course of his 19-year career, won 270 games and pitched in four World Series. At the time of his retirement, he was the last of the 17 spitballers left in the league.
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.
Grimes was the manager of the Dodgers in 1937-38, compiling a two-year record of 131-171 (.434), with his teams finishing sixth and seventh respectively in the National League. He then remained in baseball for many years as a minor league manager and a scout. He managed the Toronto Maple Leafs of the International League from 1942 to 1944, and again in 1952 and 1953, winning the pennant in 1943.
Grimes 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.'