Background <p>Adverse childhood experiences (ACEs) are recognized as a transdiagnostic risk factor for developing severe mental illnesses (SMIs), including schizophrenia (SCZ), major depressive disorder (MDD), or bipolar disorder (BD). However, the specific associations and underlying mechanisms linking ACEs and SMIs remain unclear. In recent years, oxytocin (OXT), a neuropeptide known for its role in social bonding and stress regulation, has emerged as a crucial pathway linking SMIs and ACEs. This study aimed to investigate the relationship between SMIs among individuals with a history of childhood adversity and oxytocin dysregulation both at biochemical and genetic levels.</p> Method <p>We conducted a systematic review assessing OXT measurements or the role of OXT receptor gene (<i>OXTR</i>) polymorphisms in individuals with or without SMIs and a history of ACEs. A comprehensive search of four databases (PsycINFO, MEDLINE, Web of Science, and PubMed) was undertaken, adhering to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and the review protocol was registered in PROSPERO: CRD42024555819. Comparisons were made between SMI groups and healthy controls (HCs). Data were extracted and appraised independently by two reviewers using the Mixed Methods Appraisal Tool (MMAT). Primary outcomes included group differences in ACE scores, a measure that reflects the type, quantity, and severity of childhood trauma. We also compared group differences in OXT levels, genotype frequencies of <i>OXTR</i> single-nucleotide polymorphisms (SNPs), thereby, exploring links between ACEs, OXT-OXTR signalling, and SMIs.</p> Results <p>Of 545 reports identified by the search, 14 studies with 5,624 participants met the inclusion criteria. Most studies (<i>n</i> = 13; 92.86%) reported that individuals with SMIs exhibited significantly higher ACE scores than HCs. Among the nine of fourteen studies that measured OXT levels, 66% (n = six of nine) reported lower OXT levels in SMIs irrespective of the subgroups, including in SCZ and borderline personality disorder (BPD). Several polymorphisms in <i>OXTR</i> were found to have a modulatory effect on SMI outcomes. A subset of SNPs conferred susceptibility, whereas others served as protective factors.</p> Conclusion <p>This review highlights associations between OXT system and SMIs with a history of ACE.</p>