Multiplex digital PCR (dPCR) approaches are commonly employed in wastewater-based epidemiology (WBE) studies. However, optimizing the dPCR workflow is a critical step to ensure its reliability and accuracy before application. In this study, a 6-plex Crystal Digital PCR® (cdPCR) workflow was optimized for the simultaneous detection of six epidemiologically important pathogens, including three enteric viruses, noroviruses of genogroups I and II (NoV-GI and GII) and enteroviruses (EnV), and three respiratory viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), influenza A virus (InfA), and respiratory syncytial virus B (RSVB), in wastewater. Four cDNA input ratios (20 %-70 %) and two extraction kits were evaluated for optimization, with 30 % cDNA input and the AllPrep PowerViral DNA/RNA Kit (Qiagen) exhibiting optimal performance. The optimized 6-plex cdPCR assay was applied to a year-long wastewater surveillance study in Japan (n = 52), revealing distinct trends and prevalence ratios for enteric and respiratory viruses. NoV-GII was detected in 96 % of the samples with the highest mean concentration (6.1 ± 0.6 log