Canine distemper virus (CDV) is a highly contagious pathogen and causes a fatal systemic disease in domestic dogs and wild carnivores worldwide. Despite CDV infections being monitored globally, studies on CDV in Vietnam seem to be limited. This study, therefore, investigated the epidemiological, clinical, and molecular characteristics of CDV in the Mekong Delta (MD) region of Vietnam. A total of 6687 ocular/nasal swabs were collected from CDV-suspected dogs across seven cities/provinces. CDV infection was detected in 6.19% (414 dogs) of suspected dogs using a commercially available rapid kit, with infection associated with age, roaming status, and vaccination status. Hematological and blood biochemical analysis of CDV-infected dogs revealed anemia, leukopenia, neutrophilia, thrombocytopenia, a slight increase in aspartate aminotransferase (AST) levels, and a significant increase in blood urea nitrogen (BUN) levels. Molecular characterization of partial hemagglutinin (H) and fusion (F) genes exhibited high nucleotide and amino acid homology with the Asia-1 genotype. Phylogenetic analysis confirmed that the field sequences were clustered into the Asia-1 genotype together with the neighboring countries. These findings provide important insights into the current epidemiological, clinical, and molecular features of CDV circulating in Vietnam.