IL-10 and IL-6 play important roles in protecting against inflammation and clearing pathogens from the body. In this study, homologous compounds of IL-10 and IL-6 were identified in channel catfish, and their immune responses were analyzed. The CDS sequences of IL-10 and IL-6 were 549 bp and 642 bp, respectively, and showed the highest homology with Ameiurus melas. In addition, the expression of the IL-10 and IL-6 genes was ubiquitous in 10 tissues examined. IL-10 is highly expressed in the liver and slightly expressed in the gill. The high expression of the IL-6 gene was observed in the spleen, heart, and gonad, with the lowest levels in the liver. LPS, Poly(I:C), PHA, and PMA showed a highly significant increase in IL-10 and IL-6 expression 48 h after CCK stimulation (p < 0.01). Otherwise, Yersinia ruckeri, Streptococcus iniae, channel catfish virus, and deltamethrin induced IL-10 and IL-6 expression, varying in intensity between different organs. Our results suggest that IL-10 and IL-6 are involved in the immune response of the host against the pathogen.