Background: Single-sport athletes who specialize in baseball at a young age may have a greater predisposition to overuse injury, burnout, and decreased career longevity when compared with multiple-sport athletes. The effect of sport specialization has not been studied in professional baseball players. Hypothesis: Major League Baseball (MLB) players who played multiple sports in high school would experience fewer injuries, spend less time on the disabled list, play more games, and have a longer career than athletes who played only baseball in high school. Study Design: Descriptive epidemiology study. Methods: First- and second-round MLB draft picks from 2008 to 2016 who played in at least 1 professional game were included in this study. Athletes who participated in 1 or more sports in addition to baseball during high school were considered multisport athletes, and athletes who participated in only baseball were considered single-sport athletes. For each athlete, participation in high school sports, injuries sustained in MLB and Minor League Baseball, number of days on the disabled list for each injury, number of games played in both leagues, and whether the athlete was still active were collected from publicly available records. Results: A total of 746 athletes were included in this study: 240 (32%) multisport and 506 (68%) single sport. Multisport athletes played in significantly more mean total games (362.8 vs 300.8; P < .01) as well as more mean MLB games (95.9 vs 71.6; P = .04) than single-sport athletes. There was no difference in the mean number of seasons played in the major leagues (1.8 vs 1.6; P = .15) or minor league (5.25 vs 5.20; P = .23) between multisport and single-sport athletes. Single-sport athletes had a significantly higher prevalence of upper extremity injuries compared with multisport athletes (136 [63%] vs 55 [50%]; P = .009). Single-sport pitchers also had a higher prevalence of shoulder and elbow injuries (86 vs 27; P = .008) and were more likely to have recurrent elbow injuries (33% vs 17% recurrence; P = .002) compared with multisport pitchers. Conclusion: Professional baseball players who participated in multiple sports in high school played in more major league games and experienced lower rates of upper and lower extremity injuries than players who played only baseball in high school.