The COVID-19 pandemic highlighted the urgent need for genomic surveillance to monitor viral evolution and guide public health responses, especially in limited-resource settings. This study describes the establishment and implementation of a SARS-CoV-2 genomic surveillance system by Pasteur Institute in Ho Chi Minh City (PIHCM), covering 20 provinces in southern Vietnam from January 2020 to June 2023. Nasopharyngeal swabs were systematically collected, screened by RT-PCR (Ct < 28), and sequenced using adaptable Next-Generation Sequencing technologies, including Illumina MiSeq and later Oxford Nanopore MinION, supported by international training and resources. Phylogenetic analyses tracked viral lineage dynamics across five pandemic phases. A total of 2207 genomes were sequenced, revealing temporal shifts in variant dominance, particularly Delta and Omicron variants and an average mutation count of 52.5 per sample. The data were instrumental in managing local outbreaks, informing national responses, and contributing to global databases like GISAID. This study demonstrates that adaptive genomic surveillance is both feasible and effective in resource-constrained settings. It underscores the critical role of real-time genomic data in pandemic response and advocates for sustained investment in capacity building, infrastructure and global collaboration, offering a scalable model for future preparedness in low - and middle - income countries.