Golden pompano (Trachinotus ovatus) has become an economically important fish in China in the past decade. However, Cryptocaryon irritans, a parasitic ciliate, causes considerable economic losses in the mariculture of T. ovatus. To characterize the pathogenesis of C. irritans in T. ovatus, the pathological properties, immune-related enzyme activity and expression of the NEMO gene was analysed. The results from the histological sections showed that there was considerable metamorphosis and hyperplasia in the parasitized sites (skin) with leukocyte aggregation and mucous cell increases after C. irritans infection. Moreover, the activities of four enzymes, that is, alkaline phosphatase (AKP), acid phosphatase (ACP), superoxide dismutase (SOD) and lysozyme (LZM), were significantly increased in different tissues after C. irritans infection. Furthermore, the ORF of T. ovatus NF-kappa-B essential modulator (ToNEMO) measures 1650 bp, encoding 548 amino acids. The ToNEMO transcripts were universally expressed in all examined tissues, with higher levels being observed in the immune-relevant and central nervous tissues. The mRNA levels of ToNEMO after C. irritans infection were significantly increased in the gill, skin, liver, spleen and head kidney. These results suggested that ToNEMO might be involved in immune responses and helped to elucidate the physiological response after the C. irritans infection of fish.