Clostridium perfringens constitutes the normal gut microbiome in pigs; however, it can potentially cause pre- and post-weaning diarrhea. Nevertheless, the importance of this bacterium as a primary pathogen of diarrhea in piglets needs to be better understand, and the epidemiology of C. perfringens in Korean pig populations is unknown. To study the prevalence and typing of C. perfringens, 203 fecal samples were collected from diarrheal piglets in 61 swine farms during 2021–2022 and examined for the presence of C. perfringens and enteric viruses, including porcine epidemic diarrhea virus (PEDV). We determined that the most frequently identified type of C. perfringens was C. perfringens type A (CPA; 31.5%). Among them, the single-infection of CPA (46.9%) and co-infection of CPA with PEDV (45.3%) were most common in diarrheal samples. Furthermore, we conducted animal experiments to investigate the clinical outcomes of single- and co-infections of highly pathogenic (HP)-PEDV and CPA in weaned piglets. Our results illustrated that the pigs infected with HP-PEDV or CPA showed no or mild diarrhea without mortality. However, the animals co-inoculated with HP-PEDV and CPA underwent more severe diarrheal symptoms when compared to those of the single-infection pigs. Additionally, CPA promoted PEDV replication in co-infected piglets with evidence of high viral titers in the feces. A histopathological examination revealed more severe villous atrophy in the small intestine of co-infected pigs than in single-infection pigs. There were obvious synergistic clinical implications between PEDV and CPA co-infection in weaned piglets.