Hand-foot-and-mouth disease (HFMD), and herpangina (HA) are common pediatric diseases mainly caused by infection of enteroviruses (EVs). Therefore, clarifying the molecular epidemiology of EVs in HFMD and HA outbreaks is important for understanding the etiological characteristics of the diseases and facilitating the treatment. During an outbreak in 2021, throat swab samples were collected from 54 HFMD or HA patients aged (3.40±1.67) years in the Third Xiangya Hospital, Changsha, Hunan Province, China. The prevalence of EVs in the samples was evaluated by viral metagenomic sequencing (VMGS), and the serotypes of these EVs were verified by PCR amplification of vp1 region followed by Sanger sequencing. Complete genomes of representative EV strains were further sequenced for phylogenetic analyses. For coxsackievirus (CV) A4, the predominant serotype in this outbreak, the amino acid sequences of VP1 were subjected to mutation analysis and immune epitope prediction. VMGS results revealed that sequence reads of EV genomes accounted for 98.29% of all the reads. PCR testing confirmed EV in 47 out of the 54 samples, representing an EV positive rate of 87.04%. Five EV serotypes were identified, including CVA2 (7, 14.89%), CVA4 (22, 46.81%), CVA10 (4, 8.51%), CVA16 (7, 14.89%), and CVB3 (3, 6.38%). Additionally, EV serotypes were undetermined in 4 EN-positive samples (8.51%). HFMD cases were tested positive for CVA4 and CVA16 only, while HA cases included all five serotypes.11 representative EV genomes revealed nucleotide sequence identities ranging from 96.57% to 99.04%, compared to the closest reference strains. VP1 of CVA4, the predominant serotype, harbored 8 amino acid variation sites among which 2 were located within the predicted MHC class-I epitopes. This study characterized the serotype distribution and mutation profiles of EVs in pediatric HFMD and HA cases during the 2021 Changsha outbreak, providing critical data for local epidemiological surveillance. Amino acid sequence analysis of CVA4’s VP1 protein revealed persistent changes in immunogenic epitopes, suggesting viral adaptation to immune pressure — a finding with significant implications for vaccine development. Consequently, sustained molecular surveillance during outbreaks is essential to formulate effective prevention and control strategies.