This study was conducted to investigate the effects of replacing dietary fish oil (FO) with palm oil (PO) in juvenile Nile tilapia, Oreochromis niloticus (9.34± 0.02g initial weight) with emphasis on growth performance, digestive enzyme activities as well as serum biochemical parameters. Also, lysozyme activity (LYZ), respiratory burst (RB), superoxide dismutase (SOD), catalase (CAT) and resistance to Streptococcus iniae were investigated. Fish were stocked in 15 rectangular fiber glass tanks (150× 60× 40 cm) at 40 fish per tank with water maintained at 210 litres. Fish were fed five isonitrogenous (33% crude protein) and isolipidic (10% lipid) diets with PO included at 0% (0% PO), 25% (25% PO), 50% (50%PO), 75% (75% PO) and 100% (100% PO) for 8 weeks. The findings demonstrated that growth, and feed utilization was not compromised when PO was used in place of FO either partially or totally. Except for protease activity which was not significantly altered, lipase and amylase activities were significantly altered when FO was replaced with PO. There were no significant differences among treatments for CAT, SOD and LYZ. Serum malondialdehyde (MDA) in fish fed 100% PO was significantly lower than all other groups whiles total antioxidant capacity (TAC) of fish fed 0% PO was significantly higher than all other groups. Fish fed 0% PO, 25% PO and 50% PO had glutathione reductase (GR) significantly higher than fish fed 75% PO and 100% PO. RB in fish fed 0% PO were significantly lower than fish fed 75% PO and 100% PO. Also, fish fed 0% PO had significantly lower total protein (TP) compared with groups fed 50% PO and 75% PO. Fish fed diets with PO had similar resistance ability to Streptococcus iniae as those fed diets with FO. However, the liver function was likely to be compromised due to the increase in aspartate amino transferase (AST) and alkaline phosphatas (ALP) along increasing PO inclusion levels. AST, total protein, triacylglycerol (TAG) and low-density lipoprotein cholesterol (LDL-C) were significantly higher (p<0.05) in groups fed higher levels of PO. This study therefore concludes that feeding tilapia fingerlings with diets containing PO affects antioxidant and innate immune parameters negatively due to the reduction in LYS, TAC, GR, MDA, CAT, SOD and GSHpx.