The expression of immune‐related genes and immune responses to Aeromonas hydrophila were investigated on Oreochromis niloticus (6.07 ± 0.07 g), by feeding them six different diets for 8 weeks to apparent satiation. Diets contained fish oil (60g/kg FO), virgin coconut oil (60g/kg VCO) and corn oil (60g/kg CO) as sole lipids or blends of 30g/kg FO + 30g/kg VCO (3FVCO), 30g/kg FO + 30g/kg CO (3FCO) and 30g/kg VCO + 30g/kg CO (VO). Fish fed 3FCO recorded higher final weight, percentage weight gain (%WG) and specific growth rate (%SGR) but not significantly higher than all other groups. Triglyceride was higher in fish fed 3FCO than 3FVCO and CO (p ˂ 0.05), whereas total immunoglobulin (TIg) was not significant (p ˂ 0.05) between groups. Lysozyme activity was significantly higher in fish fed diet CO while groups FO, 3FCO and VCO recorded the least activities (p ˂ 0.05). Although alternative complement activity (ACH50), complement proteins (C3 and C4), was not influenced, antibody titre production was significantly higher in fish fed diet 3FCO and lower in group CO. mRNA expression of IL‐1β was significantly upregulated in fish fed VO while the expression of C‐type lysozyme and TGF‐β was not significantly influenced across treatments, although group fed FO recorded higher expression levels, respectively. Lower mortalities of fish were recorded in groups fed 3FCO and VO after 14 days postchallenge with A. hydrophila disease indicating the enhancing effects of vegetable oils to boost immune response and resistance to disease. The study concludes that alternative lipid sources with high polyunsaturated fatty acids (PUFAs‐ALA and LA) (CO) and blend of saturated fatty acids (SFA)(VCO) can partially and or exclusively replace FO with an improved effect on tilapia and resistance to A. hydrophila in tilapia.