Background: Mental ill health is persistent and pervasive throughout universities worldwide, with consequent calls for whole-of-university approaches to improve mental health and wellbeing throughout all levels and areas of the institutional setting. However, rather than addressing setting-level factors, most research focuses on individual-level intervention and change. The literature on setting-level change consequently remains limited and under-synthesised.Aim: To identify the domains of setting-level change – particularly focusing on institutional policies, systems, and environments (PSE) – evaluated for mental health impacts in universities, and to synthesise the ways in which PSE changes affect student and staff mental health and wellbeing.Method: A systematic mixed studies review, searching APA PsycINFO, MEDLINE via Ovid, and Web of Science, was conducted. Qualitative, quantitative, and mixed-methods studies, investigating mental health outcomes, perspectives, and experiences arising from PSE changes in university settings, were included. Included studies were critically appraised using the Mixed Methods Appraisal Tool.Findings: Eighteen studies (three qualitative, six quantitative, and nine mixed-methods) were included in this review. All studies evaluated PSE changes in relation to students’ mental health and wellbeing. Two domains of PSE changes were identified: (1) learning and teaching, and (2) student-focused policy. Most studies demonstrated moderate to high risk of bias.Conclusion: There is mixed evidence on how PSE changes in universities affect students’ mental health and wellbeing, and further research is needed on the impacts of PSE changes upon staff. There is also a need for greater adoption of more rigorous, complexity-oriented study designs.