Summary The objective of this study was to evaluate differential expression of innate and adaptive immune genes, including immunoglobulin, immune cell receptor, cytokine, inflammatory protein, toll‐like receptors (TLR) and recombination‐activating gene (RAG) in skin from channel catfish, Ictalurus punctatus after immunization with live theronts of Ichthyophthirius multifiliis (Ich) by intraperitoneal injection. The immunized catfish showed significantly higher survival rate (95%) than those of mock‐immunized control fish (0% survival) after the theront challenge. The gene expression of innate immune system, such as cytokines (IL‐1β type a, IL‐1β type b, IFN‐γ, TGF1‐β and TNF‐α) and inflammatory proteins (NF‐kB and iNOS 2), showed significant upregulation at day 1 (D1) post‐immunization. Expression of TLR genes exhibited a rapid increase from hour 4 (h4) to D10 post‐immunization. Genes of the adaptive response, such as the cell receptor MHC I, CD8+, CD4+ and TCR‐α, showed upregulation at D1, D6 and D10. The TCR‐β expression increased rapidly at h4 and remained upregulated until D10. Immunoglobulin IgM upregulation was detected from h4 until D2 while IgD expression was increased from D1 until D10. Rapid upregulation of innate and adaptive immune genes in skin of catfish following live theront vaccination was demonstrated in this study ultimately resulting in significant protection against Ich infection.