Background: Although there is a growing focus on the mental well-being of licensed clinicians, there remains a scarcity of comprehensive evidence concerning the mental well-being of personal support workers (broadly defined as direct care workers), a vital segment of the healthcare workforce, particularly for aging populations. This review aims to identify, summarize, and synthesize the literature on work-related stressors associated with mental health problems among personal support workers, while also examining the potential influence of gender or sex differences in this relationship. Methods: This systematic review searched the EMBASE, PsycINFO, PubMed/Medline, and Web of Science databases for relevant studies. Studies published between 1 January 2003 and 30 June 2024 were included in the review. A quality assessment of each study was conducted using the Joanna Briggs Institute Checklist for Analytical Cross-Sectional Studies and the Joanna Briggs Institute Critical Appraisal Checklist for Cohort Studies. Meta-analysis was not performed due to the heterogeneity of the studies' characteristics. Results: Fourteen (14) articles met the inclusion criteria. They assessed burnout, depression, and/or anxiety among personal support workers who were exposed to various work-related stressors including high workload, aggressive client behavior, insufficient resources (e.g., physical and staffing), role ambiguity, conflict, personal growth, job satisfaction, discrimination, lack of co-workers or supervisors support, emotional suppression, extended working hours, complicated grief, and organizational support or respect. Aggressive client behavior, role ambiguity, resource inadequacy, and high workload emerged as the most frequently reported stressors. Burnout was the most frequently observed outcome. These relationships persisted in many multivariable analyses, even after adjusting for potential confounders. Also, females who experienced work-related stressors were more likely than males to report burnout, depression, or anxiety. Limitations: The considerable heterogeneity of various work-related stressors and measurements among selected studies prevented a meta-analysis. Conclusions: Collectively, this review's results suggest a significant association between major work-related stressors and mental disorders among personal support workers, while also emphasizing notable gender/sex differences in this relationship. These findings not only guide future research into the mental well-being of personal support workers but also underscore the importance for healthcare institutions of implementing organizational interventions to mitigate stressors and cultivate a more supportive work environment.