Objective: To analyze the phylogenetic characteristics of VP1 gene of Coxsackievirus A10 (CVA10) isolates from 2004 to 2023, and to understand the genetic evolution and epidemic trends of CVA10, so as to provide references for the prevention and control of hand, foot, and mouth disease. Methods: The full-length sequences of the VP1 region of CVA10 isolates were retrieved from the BV-BRC database before December 15, 2024. Gene typing, sequence analysis, evolutionary analysis, and amino acid mutation site analysis were conducted using bioinformatics software. Results: A total of 1 253 CVA10 isolates VP1 region nucleotide full-length sequences from 2004 to 2023 were included, with 9 strains from 2004 to 2008, 338 strains from 2009 to 2012, and 906 strains from 2013 to 2023. China had the highest number of CVA10 isolates, with 1 143 strains accounting for 91.22%, and the predominant genotype was C3. Compared to the prototype strain, the nucleotide sequence homology of the VP1 region of CVA10 isolates ranged from 74.94% to 77.63%, while the amino acid sequence homology ranged from 88.59% to 93.62%. The third codon position preferred cytosine and thymine. The top three most abundant amino acids were threonine, alanine, and valine. The average relative synonymous codon usage of 30 amino acid codon groups was greater than 1. The average amino acid substitution entropy value was 0.04, with four amino acid mutation-prone sites identified, and the mutation-prone rate was 1.35%. Conclusions From 2004 to 2023, the majority of CVA10 isolates were primarily sourced from China, with genotype C3 being the predominant circulating strain in China. The nucleotide homology between the CVA10 isolates and the prototype strain was relatively low, and mutation-prone sites were identified, indicating that enhanced monitoring of viral variation is necessary.