Background Significant increases in injuries were observed in the 2020 Major League Baseball (MLB) season; these were attributed to an increased acute to chronic workload due to the interrupted preseason and compressed season during the coronavirus disease of 2019 (COVID-19) pandemic. In 2021, the MLB resumed its regular schedule. Hypothesis/Purpose The purpose of this study was to determine the injury incidence and epidemiology of the 2021 MLB season compared to the injury incidence in the 2020 season and pre-COVID-19 seasons. The hypothesis was that, with the return to normal preseason training, injury incidence in 2021 would return to pre-COVID-19 rates. Additionally, it was hypothesized that injury list (IL) placements at midseason 2021 would be decreased relative to 2020 due to the uninterrupted preseason yet increased at full season 2021 due to increased overall workload from 2020. Study Design Descriptive epidemiology study Methods The MLB transactions database was searched for players placed on the IL between 2018 and 2021. Injuries were categorized by body part and player position. Incidence per 1000 athlete-exposures was calculated for the pre-COVID-19 (2018-2019), 2020, and 2021 seasons. The z test for proportions was used to determine significant differences between injury incidences. Results The injury incidence rate by midseason 2021 (9.32) compared to 2020 (8.66) was not significantly different (p=0.234). At full season 2021, injury incidence rate (8.69) was significantly higher than pre-COVID-19 seasons (5.13, p<0.001), but not 2020 (p=0.952). When comparing full season 2021 to 2020, increased foot/ankle (0.50 vs 0.14, respectively, p<0.001) and miscellaneous (1.92 vs 0.68, respectively, p<0.001) injuries were observed. Conclusion The overall injury incidence in 2021 was significantly higher than pre-COVID-19 seasons, and no significant difference was observed between both mid- and full season 2021 and 2020, refuting the hypotheses. This signifies that injury incidence remained elevated in the 2021 season despite resumption of preseason training and a regular season. Level of Evidence 3