Objective: To provide updated evidence on prognostic factors for return to work (RTW) in the early and late phases after acute orthopedic trauma from a biopsychosocial perspective. Methods: A systematic review of articles indexed in the MEDLINE, CINAHL, and Embase databases between 2010 and 2020 was performed. The inclusion criteria were cohort studies of employed populations sustaining acute orthopedic trauma with follow-up data on RTW. Biopsychosocial prognostic factors for RTW must be reported in the multiple regression models and divided into early (≤ 6 months) and late phases (> 6 months) postinjury. Two reviewers performed study selection, assessed the risk of bias and quality using the Quality in Prognosis Studies (QUIPS) tool and the Newcastle–Ottawa Scale (NOS), and extracted data independently. Results: Thirty articles were included with a follow-up period of 1–58 months. Based on the QUIPS tool, 7 studies (23%) were considered to have a low risk of bias, and 21 studies (70%) were considered to have a moderate risk of bias. Based on the NOS, the quality was high in 87% of the included studies. The RTW rates ranged from 22% to 74% in the early phase and from 44% to 94% in the late phase. In the early phase, strong evidence was found for injury severity. In the late phase, strong evidence was found for age, injury severity, level of pain, self-efficacy, educational level, blue-collar work, and compensation status; moderate evidence was found for recovery expectations and physical workload. There was limited or inconsistent evidence for the other factors. Conclusion: Based on the levels of evidence, injury severity should be considered as one of the key barriers to RTW in the early and late phases postinjury. This finding underlines the need for serious injury prevention efforts. Our results also emphasize the multifaceted actions of the biopsychosocial model to facilitate RTW: promoting policies for older injured workers, improving access to medical and rehabilitation facilities, and adapting physical workload. Multiple other factors are likely important but require additional high-quality studies to assess their role in the RTW process.