Purpose: Psychological factors have shown to be predictors of injury in professional football. However, it seems that this is a two-way relationship, as severe musculoskeletal time-loss injuries have shown to be associated with the onset of symptoms of common mental disorders (CMD). There is no longitudinal study performed exploring this interaction between symptoms of CMD and injuries. The purpose of this study was to explore the interaction between severe musculoskeletal time-loss injuries and symptoms of CMD in professional football players over a 12-month period. Methods: Players were recruited by their national players’ unions in five European countries. Symptoms of CMD included in the study were related to distress, anxiety/depression, sleep disturbance and adverse alcohol use. Results: A total of 384 professional football players were enrolled in the study, of whom 262 (68%) completed the 12-month follow-up period. The mean age of the participants at baseline was 27 ± 5 years, and they had played professional football for 8 ± 5 years on average. Symptoms of CMD at baseline were not associated with the onset of severe musculoskeletal time-loss injuries during the follow-up period with relative risks (and 95% CI) ranging from 0.6 (0.3–1.0) to 1.0 (0.5–2.2). In contrast, severe musculoskeletal time-loss injuries reported at baseline were associated with the onset of symptoms of CMD during the follow-up period with relative risks ranging from 1.8 (0.8–3.7) to 6.9 (4.0–11.9). Conclusion: No relationship was found between symptoms of CMD and the onset of severe musculoskeletal time-loss injuries. However, professional football players who suffered from severe musculoskeletal time-loss injuries are likely to develop subsequent symptoms of CMD. This study emphasizes the need for an interdisciplinary medical approach, which not only focuses on the physical but also on the mental health of professional football players. An early identification of players at risk of symptoms of CMD, such as those suffering from severe musculoskeletal injuries, creates the opportunity for an interdisciplinary clinical medical team to treat the players timely and adequately. Level of evidence: Prospective cohort study, Level II.