The workplace is a vital setting to support positive mental health. Mental health conditions in the workforce contribute to decreased work engagement and participation. There is existing literature on return-to-work (RTW) interventions for individuals with work-related mental health conditions, however, there lacks consensus on their effectiveness. Therefore, the primary aim of this systematic review was to synthesize the literature and evaluate the effectiveness of return-to-work interventions on return-to-work rates, quality of life, and psychological wellbeing for individuals with work-related mental health conditions. Selected articles were organized and identified using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and the Population/Intervention/Comparison/Outcome (PICO) framework. Quality assessment of the included studies was completed using the Critical Appraisal Skills Programme randomized controlled trials checklist and the Joanna Briggs Institute quasi-experimental studies checklist. A random effects meta-analysis model was performed using DerSimonian-Laird weighting to calculate standard mean difference and risk ratios to assess the impact of RTW interventions on return-to-work rates, absenteeism, stress symptoms, depression symptoms, and quality of life. A total of 28 out of 26,153 articles met the inclusion criteria. Diagnoses for participants in the studies ranged from work-related stress to work-related PTSD following exposure to a psychologically traumatizing event in the workplace. No significant differences were found for the meta-analyses examining return-to-work rates, absenteeism, depression, stress, and quality of life. The most effective interventions were found to be a multi-domain intervention (67% of participants RTW full time) and a health-focused intervention (85% RTW rate). Future research may consider establishing effective interventions to develop programs or policies supporting the RTW of employees and promote mental well-being among employees experiencing work-related mental health conditions.