It is currently unknown which genetic polymorphisms are involved in substance use disorder (SUD) comorbid with bipolar disorder (BD). The research on polymorphisms in BD comorbid with SUD (BD + SUD) is summarized in this systematic review. We looked for case-control studies that genetically compared adults and adolescents with BD and SUD, healthy controls, and BD without SUD. PRISMA was used to create our protocol, which is PROSPERO-registered (identification: CRD4221270818). The following bibliographic databases were searched indefinitely until December 2021 to identify potentially relevant articles: PubMed, PsycINFO, Scopus, and Web of Science. This systematic review, after the qualitative analysis of the study selection, included 17 eligible articles. In the selected studies, 66 polymorphisms in 29 genes were investigated. The present work delivers a group of potentially valuable genetic polymorphisms associated with BD + SUD: rs11600996 (), rs228642/rs228682/rs2640909 (), PONQ192R (), rs945032 (), rs1131339 (), and rs6971 (). It is important to note that none of those findings have been confirmed by two or more studies; thus, we believe that all the polymorphisms identified in this review require additional evidence to be confirmed.