Background Acute diarrhea contributes to a significant global burden of disease. However, the infection or co-infection patterns of enteropathogens, along with their age dependence and clinical effects, remain ambiguous. Methods A nationwide sentinel surveillance was conducted in all-age patients with acute diarrhea in China from 2009 to 2020. The clinical severity was assessed using a modified Vesikari score method, which categorized cases into moderate-to-severe diarrhea (MSD) or mild diarrhea. The association between clinical severity and age-specific patterns of enteropathogenic infections and co-infections was analyzed through a binary logistic regression model. Results A total of 195,988 individuals were enrolled and tested for 17 enteropathogens, among whom 27,358 (13.96%) patients developed MSD. In comparison to patients with mild diarrhea, MSD patients showed significantly higher rates of viral-bacterial co-infection in adults and older adults, as well as higher rates of viral-viral co-infection across almost all age groups except children aged < 6 months. The multivariate analyses revealed a significantly distinct pattern in the infections and co-infections of viral and bacterial enteropathogens associated with MSD between children and adults. Conclusion These findings highlight the age-specific patterns of enteropathogen infection among cases of MSD and mild diarrhea and underscore the necessity for age-related strategies in vaccine schedules, clinical diagnosis and treatment.