The major histocompatibility complex (MHC) genes show high polymorphisms in vertebrates depending on animal immunity status. Herein, MHC class IIA gene in Aeromonas hydrophila-challenged Nile tilapia was screened for presence of polymorphisms using sequencing. Twelve nucleotides deletion polymorphism was determined with a PCR product size of 267 bp in the resistant fish and 255 bp in the control and susceptible/diseased fish. Additionally, a non-synonymous right frameshift c.712 T > G (P. 238 * > G) SNP was detected at the stop codon (*). SNP-susceptibility association analysis revealed that fish carrying GG genotype and allele G were high susceptible (risk) for A. hydrophila, and had lower immune response as indicated by significant reduction in non-specific immune parameters (total protein, globulin, IgM, phagocytic activity, phagocytic index, and lysosome activity) and mRNA level of MHC IIA, interleukin 1 beta (IL1β), tumor necrosis factor alfa (TNFα), and toll-like receptor 7 (TLR7) in the spleen and head kidney. Thus, G allele could be considered as a risk (recessive or mutant) allele for c. 712 T > G (P. 238 * > G) SNP and so selection of Nile tilapia with protective allele (T) for this SNP could improve the disease resistant of the fish.