Introduction The purpose of this study is to evaluate the rates of regular season soft tissue injuries in National Football League (NFL) players during the 2020 season, which had a canceled preseason due to the COVID-19 pandemic. Methods This study retrospectively reviewed the injury rates of the 2020-2021 NFL regular season in comparison to the 2018-2019 NFL regular season using publicly available injury data. The focus of our analysis was comparing the following soft tissue injuries: hamstring, groin, calf, quadriceps, thigh, knee - anterior cruciate ligament (ACL), pectoral, and Achilles. The week of injury occurrence, duration of injury in weeks, position of the injured player, and age of the NFL player at injury were obtained. Injury rates were calculated per 1000 athletic exposures with 95% confidence intervals (CIs). A chi-square test and Student's t-test were utilized as appropriate. Results There were 1370 total injuries in the 2018-2019 regular NFL season and 2086 total injuries reported in the 2020-2021 regular NFL season. The total number of injuries per 1000 athletic exposures was significantly higher in the 2020-2021 NFL season compared to the 2018-2019 NFL season (88.57 versus 58.17, p < 0.001). The rates of injuries per 1000 athletic exposures for hamstring (9.98 versus 5.31, p = 0.043), groin (5.56 versus 2.46, p = 0.007), calf (4.08 versus 1.61, p = 0.006), quadriceps (2.00 versus 0.72, p = 0.030), and thigh (1.23 versus 0.30, p = 0.012) injuries were significantly higher in the 2020-2021 regular NFL season compared to the 2018-2019 NFL regular season. Conclusions The 2020-2021 NFL season had a significantly higher incidence of soft tissue injuries compared to the 2018-2019 regular NFL season, which may have been associated with the absent preseason due to the COVID-19 pandemic and an abrupt increase in the athletic workload of players.