The objective of this study is to report the complete-genome sequence of a field African swine fever (ASF) virus (ASFV), namely ASF/VN/CanTho-OM/2021, which caused a fatal outbreak in domestic pigs in the Mekong Delta. Complete-genome sequencing detected an 18 bp nucleotide deletion in the EP402R gene (encoding for serotype-specific proteins CD2v) of ASF/VN/CanTho-OM/2021, which was determined to belong to genotype 2 and serotype 8. This mutation pattern was confirmed as unique in GenBank; thus, ASF/VN/CanTho-OM/2021 can be considered a novel variant, with a potential change of sero-characteristics within genotype 2. An additional unique mutation of 78 bp nucleotide insertion was also observed in the B475L gene. Additionally, four copies of tandem repeat sequences were found in the intergenic region (IGR) located between I73R and I329L, previously assigned as the IGR III variant. This study is the first to report the complete genome of ASFV in the Mekong Delta, and it highlights the necessity of strengthening molecular surveillance to provide further knowledge on the evolution and incursion of ASFV in the Mekong Delta and Vietnam.