Background <p>Sudan is one of the few African countries reporting increasing <i>Plasmodium vivax</i> infections despite the high prevalence of the Duffy-negative phenotype, historically considered protective against this parasite. Emerging molecular evidence challenges this paradigm. The objective of this systematic review and meta-analysis was to synthesize evidence on the prevalence and geographic distribution of <i>P. vivax</i> infection, Duffy antigen polymorphisms, parasite genetic adaptations, and diagnostic limitations in Sudan.</p> Methods <p>This review followed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and was registered in PROSPERO (CRD42025127714). The reports of <i>P. vivax</i> infection in Sudan focusing on host Duffy status and the parasite genetic variability from 2005 to 2025 were identified through systematic searches of PubMed, Web of Science, Scopus, and EMBASE with predefined Boolean search operators. To determine the risk of bias, the Joanna Briggs Institute prevalence study checklist was employed. To obtain a pooled prevalence estimate in Duffy-negative individuals, a random-effects meta-analysis (DerSimonian-Laird estimator) was conducted. Heterogeneity was assessed using Cochran’s Q test and the I² statistic, while publication bias was evaluated using funnel plots and Egger’s regression test.</p> Results <p>A total of sixteen studies conducted between 2005 and 2025, including 5,753 participants from various regions of Sudan, were included. <i>P. vivax</i> infection was reported in both Duffy-positive and Duffy-negative individuals. Meta-analysis of five studies reporting host Duffy antigen status showed a pooled prevalence of <i>P. vivax</i> infection of 11.7% (95% CI 7.2–17.3%) among Duffy-negative individuals. The studies showed moderate heterogeneity (I² = 56%). Substantial genetic diversity was observed in the <i>P. vivax</i> Duffy Binding Protein (<i>PvDBP</i>), including multiple haplotypes and both Malagasy-type and Cambodian-type gene duplications. Most studies were assessed as having low to moderate risk of bias, and funnel plot inspection did not suggest substantial publication bias, although interpretation is limited by the small number of studies.</p> Conclusions <p>This systematic review and meta-analysis provide evidence that <i>P. vivax</i> infection occurs among Duffy-negative individuals in Sudan, challenging the long-standing assumption of complete Duffy-mediated protection. The observed parasite genetic diversity highlights adaptive mechanisms that may facilitate infection in Duffy-negative hosts. Strengthening molecular surveillance and integrating host–parasite genomic data into national malaria control programs will be critical to inform malaria elimination strategies and vaccine development in Africa.</p> Graphical Abstract <p></p>