INTRODUCTION: Depression is one of the most common yet underdiagnosed perinatal complications and our understanding of the pathophysiology remains limited. Though perinatal depression is considered to have a multifactorial etiology, integrative approaches to investigation are minimal. This review takes an integrative approach to systematically evaluate determinants and potential interactions among determinants of perinatal depression across four domains (i.e., biological, behavioral, environmental, social) and appraise the quality of methods applied. METHODS: Four databases (i.e., PubMed, CINAHL, APA PsycInfo, and Web of Science) were systematically searched to identify studies examining determinants of perinatal depression in adult perinatal persons (≥ 18 years). Articles were excluded if the outcomes were not focused on perinatal persons and depression or depression symptoms, the evaluation of depression was specific to a discrete facet of the perinatal period with probable psychological consequences (e.g., abortion, fetal/infant loss, adoption), or was considered grey literature. The Critical Appraisal Skills Programme and AXIS tools were used to guide and standardize quality appraisal assessments and determine the level of risk of bias. RESULTS: Of the 454 articles identified, 25 articles were included for final review. A total of 14 categories of determinants were investigated: biological (5), behavioral (4), social and environmental (5). Though only 28% of studies simultaneously considered determinants under more than one domain, a pattern of interactions with the tryptophan pathway emerged when determinants across domains were aggregated. Concerns for risk of bias were noted or were unclear for three types of bias: 13 (52%) selection bias, 3 (12%) recall bias, and 24 (96%) measurement bias. CONCLUSIONS: Future research is needed to explore interactions among determinants and the tryptophan pathway; to strengthen the methods applied to this area of inquiry; and to generate evidence for best practices in reporting, selecting, and applying methods for measuring determinants and perinatal depression.