Wilhelm grew up in North Carolina, fought in World War II, and then spent several years in the minor leagues before starting his major league career at the age of 29. He was best known for his knuckleball, which enabled him to have great longevity. He appeared occasionally as a starting pitcher, but pitched mainly as a reliever. Wilhelm won 124 games, still the record for relief pitchers. He was the first pitcher to reach 200 saves, and the first to appear in 1,000 games.

Wilhelm was nearly 30 years old when he entered the major leagues, and pitched until he was nearly 50. He retired with one of the lowest career earned run averages, 2.52, in baseball history. After retiring as a player in 1972 Wilhelm held longtime coaching jobs with the New York Yankees and Atlanta Braves. He lived in Sarasota, Florida for many years, and died there in 2002.

Wilhelm was one of eleven children born to poor tenant farmers John and Ethel (née Stanley) Wilhelm in Huntersville, North Carolina. He played baseball at Cornelius High School in Cornelius, North Carolina. There, he began experimenting with a knuckleball after reading about pitcher Dutch Leonard. He felt that, because he could not throw fast, honing a knuckleball offered him his best shot at success. He used a tennis ball to practice.

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