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Hepatitis B virus (HBV) remains a major public health concern in sub-Saharan Africa, where it is highly endemic and contributes substantially to liver-related morbidity and mortality. While serological and molecular tools are important for diagnosis and clinical management, there is limited information on the diversity and distribution of HBV genotypes circulating in Ghana. This study therefore aimed to determine the epidemiology and genotypic profiling of HBV among febrile individuals in a high-endemic Ghanaian setting. A hospital-based cross-sectional study (May 2022 and February 2024) across six healthcare facilities in the Savanna Region enrolled 264 febrile patients. Serum samples were screened for HBsAg using a commercial rapid test. HBV DNA was extracted from positive samples, followed by nested PCR. Amplicons were visualized by agarose gel electrophoresis. A fragment of the HBV S gene was sequenced for genotyping. Demographic data were collected. Facilities were selected by geographic distribution and eligible patients were consecutively enrolled after consent. Of the 264 participants enrolled, 142 (53.8%) were females. The majority were aged (16–30 and 31–60 years) (n = 111, 42.0%) each, while older age groups (> 60 years) were the least represented (n = 16, 6.2%). The overall HBsAg positivity rate was 13.6% (n = 36). Among those who tested HBsAg-positive, 20 (55.6%) were PCR-positive. HBV Genotype E was predominant, accounting for 95.0% (19/20) of sequenced samples, while genotype B was detected in 5.0% (1/20). Living in an extended family household was independently associated with lower odds of HBV infection [aOR = 0.17, 95% CI (0.05–0.62), p = 0.007]. Phylogenetic analysis showed that the detected isolates clustered closely with reference strains from other West-African countries including, Nigeria, Burkina Faso, Togo and Liberia. A unique genotype B isolate clustered with strains from Asia/U.S., possibly suggesting importation. This study reports an HBV prevalence of 13.6% among febrile patients in the Savanna Region, with genotype E predominating and the rare detection of genotype B. Extended family living arrangements were associated with a reduced risk of HBV infection. These findings highlight the importance of strengthening regional sequencing capacity to enable timely genotype identification and support targeted community-based education that reinforces protective household practices, integrating both molecular and socio-behavioral evidence. Furthermore, efforts should be intensified to promote hepatitis B vaccination among adults who were not covered by childhood immunization programs.