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Golden pompano (<i>Trachinotus ovatus</i>) has become an economically important fish in China in the past decade. However, <i>Cryptocaryon irritans</i>, a parasitic ciliate, causes considerable economic losses in the mariculture of <i>T. ovatus</i>. To characterize the pathogenesis of <i>C. irritans</i> in <i>T. ovatus</i>, the pathological properties, immune-related enzyme activity and expression of the <i>NEMO</i> 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 <i>C. irritans</i> 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 <i>C. irritans</i> infection. Furthermore, the ORF of <i>T. ovatus</i> NF-kappa-B essential modulator (<i>ToNEMO</i>) measures 1650 bp, encoding 548 amino acids. The <i>ToNEMO</i> 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 <i>ToNEMO</i> after <i>C. irritans</i> infection were significantly increased in the gill, skin, liver, spleen and head kidney. These results suggested that <i>ToNEMO</i> might be involved in immune responses and helped to elucidate the physiological response after the <i>C. irritans</i> infection of fish.