Background: Viet Nam has one of the world's most diverse hepatitis C virus (HCV) epidemics, dominated by genotype 6. Understanding pre-treatment resistance-associated substitutions (RASs) particularly in under-studied genotype 6 is important for informing resistance surveillance and supporting national HCV elimination strategies. We aimed to evaluate the landscape of viral diversity and baseline RASs relevant to currently used direct-acting antivirals (DAAs) in Viet Nam. Methods: We utilised whole-genome sequencing to analyse HCV isolates from a cohort of 1649 treatment-naïve patients enrolled in six clinical studies in Viet Nam between 2013 and 2023. The study assessed genotype and subtype distribution, associations with demographic and clinical variables, and prevalence of known and putative RASs in NS3, NS5A, and NS5B relevant to DAAs used in Viet Nam. Findings: Phylogenetic analysis revealed that genotype 6 was dominant (50.3%, 829/1649). We observed distinct geographical and demographic partitioning: genotype 2 was concentrated in the south and associated with older age and HIV co-infection, while genotype 3 was clustered in the north among younger males. Clinically relevant RASs were detected in 37.9% (617/1630) of patients, with the highest burden in NS5A region. Genotypes 2 and subtype 3b demonstrated a high prevalence of subtype-specific polymorphisms occurring at previously reported resistance-associated positions. Among genotype 6 infections, subtype 6a frequently carried L28F mutation (43.3%, 181/418), whereas subtype 6e demonstrated a low prevalence of previously reported clinical RASs. Interpretation: Viet Nam is characterised by a complex, genotype 6-predominant HCV epidemic with substantial subtype-specific baseline resistance diversity. The high prevalence of subtype-defining polymorphisms observed in several genotype 2 and subtype 3b lineages highlights the importance of continued molecular surveillance and may have implications for optimisation of DAA regimen selection and resistance monitoring strategies within highly diverse HCV populations. Funding: Wellcome Trust.