Background <p>Combined oral contraceptives (COCs) are widely used among premenopausal women because of their contraceptive efficacy and favourable safety profile. However, concerns remain regarding their potential association with depressive symptoms and major depressive disorder (MDD), possibly mediated through alterations in neurochemical, inflammatory, and neurotrophic biomarkers. Hence, this study aims to provide a comprehensive synthesis of the available evidence on the link between COC and selected biomarkers associated with MDD risk and to assess whether the reported outcome is associated with the generational type of COC.</p> Methods <p>This systematic review protocol was prepared following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) 2015 statement. An extensive search will be conducted on Embase and MEDLINE through the Ovid and EBSCOhost interface. The Cochrane Library will be searched to augment relevant sources of information. Two reviewers will independently screen for eligible studies using a pre-defined criterion. The risk of bias and quality of included studies will be assessed via Cochrane risk of bias tools. The certainty of evidence will be assessed via Grading of Recommendations, Assessment, Development and Evaluation Assessment (GRADE) tool.</p> Discussion <p>The rate of depression among women of reproductive age remains alarming due to various factors related to childbearing, which may limit their economic contribution and full participation in societal development. As a result, some of these women may opt for the use of available contraceptive choices, such as COC, which are linked to the onset of MDD in high-risk individuals. More so, the change in hormonal milieu influences the secretion and physiologic role of histamine and other neurotransmitters, such as serotonin, among others, thereby contributing to an increased risk of MDD in premenopausal women. Thus, unravelling the role of COC in the secretions of these biomarkers and their contribution to the onset of MDD among premenopausal women is essential in filling the research gap that will provide insight and guidance when making informed decisions about the available contraceptive choices. The uniqueness of our review also extends to the focus on biomarker-based evidence of mood disorder risk in COC users, which may provide mechanistic insight and inform future risk-stratification research to assess the risk of MDD, both in and outside the clinical setting, among high-risk individuals.</p> Systematic review registration <p>PROSPERO CRD42021284745.</p>