ObjectiveDuring Egypt's hot summer season, Aeromonas veronii infection causes catastrophic mortality on Nile Tilapia Oreochromis niloticus farms. Egypt is ranked first in aquaculture production in Africa, sixth in aquaculture production worldwide, and third in global tilapia production. This study aimed to investigate, at the molecular level, the early innate immune responses of Nile Tilapia to experimental A. veronii infection.MethodsThe relative gene expression, co‐expression clustering, and correlation of four selected immune genes were studied by quantitative real‐time polymerase chain reaction in four organs (spleen, liver, gills, and intestine) for up to 72 h after a waterborne A. veronii challenge. The four genes studied were nucleotide‐binding oligomerization domain 1 (NOD1), lipopolysaccharide‐binding protein (LBP), natural killer‐lysin (NKL), and interleukin‐1 beta (IL‐1β).ResultThe four genes showed significant transcriptional upregulation in response to infection. At 72 h postchallenge, the highest NOD1 and IL‐1β expression levels were recorded in the spleen, whereas the highest LBP and NKL expression levels were found in the gills. Pairwise distances of the data points and the hierarchical relationship showed that NOD1 clustered with IL‐1β, whereas LBP clustered with NKL; both genes within each cluster showed a significant positive expression correlation. Tissue clustering indicated that the responses of only the gill and intestine exhibited a significant positive correlation.ConclusionThe results suggest that NOD1, LBP, NKL, and IL‐1β genes play pivotal roles in the early innate immune response of Nile Tilapia to A. veronii infection, and the postinfection expression profile trends of these genes imply tissue‐/organ‐specific responses and synchronized co‐regulation.