INTRODUCTION: This systematic review explores the hypothesis that various lipid categories and lipid metabolism-related genomic variations link to mental disorders, seeking potential clinically useful markers. METHODS: We searched PubMed, Scopus, and PsycInfo databases until October 12th, 2024, using terms related to lipidomics, lipid-related genomics, and different mental disorders, i.e., Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia (SCZ), and Obsessive-Compulsive Disorder (OCD). Eligible studies were assessed. Extracted data included author, year, methodology, outcomes, genes, and lipids linked to disorders. Bias and evidence certainty were evaluated. The systematic review adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and a registered protocol (PROSPERO: CRD42023438862). RESULTS: A total of 27 studies were included. SCZ showed alterations in 77 lipids, including triglycerides (TG), ceramides, and phosphatidylcholine, while MDD and BD exhibited 97 and 47 altered lipids, respectively, with overlap among disorders. Shared genes, such as ABCA13, DGKZ, and FADS, and pathways involving inflammation, lipid metabolism, and mitochondrial function were identified. OCD was associated with sphingolipid signaling and peroxisomal metabolism. DISCUSSION: Lipid signatures in MDD, BD, and SCZ shed light on underlying processes. Further research is needed to validate biomarkers and refine their clinical applications in precision psychiatry.