Cryptocaryoniasis, caused by the ciliate parasite Cryptocaryon irritans, poses a significant threat to the large yellow croaker (Larimichthys crocea) in intensive marine aquaculture. This study explores the interaction between skin and gill microbiota and C. irritans infection, focusing on the role of commensal microbes in disease resistance. Fish were challenged with 100 theronts per gram of body weight, leading to substantial microbial dysbiosis, characterized by decreased alpha diversity and disrupted co-occurrence networks, particularly on the skin. Post-infection, Vibrio abundance significantly increased in both gills and skin, suggesting potential for secondary infections. Conversely, lower Vibrio levels correlated with higher populations of Bdellovibrio-like organisms (BALOs), which may play a beneficial role in microbial balance. Fish showed varying susceptibility, with mildly infected individuals exhibiting less histopathological damage and a stronger immune response, indicated by elevated interleukin-1β (IL-1β) and interleukin-8 (IL-8) levels. Correlation analyses revealed significant relationships between relative infection intensity (RII) and microbial composition, with certain bacteria known for anti-eukaryotic microbial properties showing negative correlations with RII. Additionally, the abundance of nitrogen-metabolizing bacteria also correlated negatively with RII. Functional predictions indicated increased bacterial genes related to denitrification and vitamin biosynthesis post-infection. Notably, Candidatus Midichloria was identified as a potential biomarker for C. irritans infection and is thought to be an endosymbiont of C. irritans, with its presence validated through PCR analysis. These findings illuminate microbial dynamics during C. irritans infection and suggest probiotic candidates for managing cryptocaryoniasis.