Opioid use is only recommended in selected cases of musculoskeletal (MSK) injuries. We assessed factors associated with increased opioid use in MSK injuries. In a retrospective analysis of over four million workers with MSK injuries using the Swiss National Accident Insurance Fund (Suva) database, we analyzed risk factors by multivariate logistic regression. Injury severity was associated with pain medication, opioid, and strong opioid use. Whereas fractures, contusions, and ruptures had higher odds for any pain medication use, increased odds for strong opioids were observed in fractures, superficial injuries, and other injuries. Injuries of the shoulders, elbow, chest, back/spine, thorax, and pelvis/hips showed high odds for opioid use (odds ratio (OR) > 2.0). Injuries of the shoulders had higher odds for strong opioid use (OR 1.136; 95% CI 1.040–1.241). The odds for using strong opioids increased from 2008 OR 0.843 (95% confidence interval (CI) 0.798–0.891) to 2018 OR 1.503 (95% CI 1.431–1.578), compared to 2013. Injury severity, type of injury, and injured body parts influenced the use of pain medication and overall opioid use in musculoskeletal injuries. Strong opioids were more often used in fractures but also in superficial and other minor injuries, which indicates that other factors play a role when prescribing strong opioids.