In 2021, Vietnam experienced a large nationwide outbreak of COVID-19, with over 1.7 million infections and 32,000 deaths. We generated 1,303 SARS-CoV-2 whole-genome sequences, and mapped out the public health measures alongside the evolutionary trajectory of the pathogen. The Alpha variant caused sporadic outbreaks in early 2021 prior to the upsurge in cases associated with the Delta variant from June onward. The Delta variant outbreak was almost entirely confined to the AY.57 lineage, accounting for 99.2% of 1,212 Delta variant sequences, and resulting from a single introduction. Viral dispersal from the north, where it was first introduced into Vietnam, to the south, marked the start of the nationwide outbreak, with the south subsequently seeding the virus back to the other regions. Distinct AY.57 phylogenetic clusters in different regions of Vietnam were documented, pointing to the impact of in-country lockdown. Genomic surveillance is critical to inform pandemic response.