Background: Neighborhood attributes are increasingly recognized as factors shaping mental health in adults. Geographic information systems (GIS) offer an innovative approach for quantifying neighborhood attributes and studying their influence on mental health outcomes. Our aim was to describe GIS applications used in neighborhood-related mental health research and how neighborhood attributes are related to depressive symptoms or psychological distress in community-residing adults. Methods: We conducted a systematic review of studies published in English that included GIS techniques and a validated questionnaire of depressive symptoms or psychological distress. Medline, PsycInfo, Embase, Scopus, CINAHL, GEOBASE, and Compedex were searched to June 2020. Study quality was assessed by a modification of the Joanna Briggs Institute’s Checklist for Analytical Cross-sectional Studies. Results: Thirty-two studies met the inclusion criteria. Studies varied in definitions of neighborhood and GIS-derived measurements of neighborhood attributes. Neighborhood attributes were significantly associated with mental health outcomes, although findings were not consistent. Moderating factors (e.g., gender, living conditions) significantly influenced depressive symptoms or psychological distress. Conclusion: Neighborhood attributes are important factors influencing mental health in adults. Consensus may be needed on how to standardize the neighborhood unit or GIS-derived measures of neighborhoods in order to explain depression or psychological distress in diverse adult populations.