Porcine deltacoronavirus (PDCoV) has emerged as a significant issue in multiple pork-producing countries. This study isolated a novel PDCoV strain, GNU-2105/KOR/2021, which caused a severe diarrhea outbreak with a high mortality rate among neonatal piglets in South Korea. The growth properties and sialic acid dependency of the GNU-2105 strain in cell culture were comparable to those of the 2016 domestic isolate, KNU-1607. Interestingly, phylogenetic analysis using the complete genome of GNU-2105 identified in 2021 demonstrated that this novel strain belongs to the US/South Korean/Japanese clade; however, it is more closely placed around the Chinese isolates. To investigate the potential pathogenic diversity between the previous and recent PDCoVs, we performed an experimental infection using conventional suckling piglets with KNU-1607 or GNU-2105. The KNU-1607-inoculated piglets suffered from acute, watery diarrhea; however, all piglets recovered and survived. In the KNU-1607-inoculated group, histopathological observation detected viral antigens in the jejunum and ileum. However, the virulence of the GNU-2105 virus was enhanced and presented severe clinical symptoms, including thin, transparent intestinal walls, with 100% mortality in piglets. Furthermore, viruses and severe villous atrophy were observed from the duodenum to the colon in all the piglets inoculated with GNU-2105 by quantitative RT-PCR and microscopic assessments, confirming the high enteropathogenicity of PDCoV in neonatal piglets. These findings could expand our understanding of the genetic and pathogenic variation of the PDCoV strain and highlight the necessity of vaccine development providing protection against virulent PDCoV.