Introduction The negative impacts of mental health disorders on the well-being of women and their infants are clear. However, less is known about the relationship between returning to work after giving birth and mental health. Previous reviews examined the relationship between maternity leave and mental health, but we defined return to work as the process of returning to part-time or full-time work after giving birth and caring for infant. This systematic review aims to: (1) describe operational definitions for return to work and (2) describe the evidence on the relationship between return to work and maternal mental health. Methods We searched PubMed, PsycINFO, CINAHL, and Web of Science for peer-reviewed studies. Articles were selected if they were published within the past 20 years, examined at least one mental health condition (e.g., depression, anxiety), and included a study sample of U.S. working mothers. Results We identified 20 articles published between 2001 and 2020. We found conflicting evidence from longitudinal and cross-sectional data demonstrating that return to work was associated with improvements and negative consequences to mental health. Work-related predictors of mental health included: access to paid maternity leave, work-family conflict, total workload, job flexibility, and coworker support. Discussion This review provides evidence that return to work and mental health are related, though the study samples have limited generalizability to all U.S. working mothers. More research is needed to understand the direction of this relationship throughout the perinatal period and how return to work affects other mental health conditions (e.g., anxiety, stress).