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The quest to reduce dependency on fish‐ or vegetable‐based oil resources has prompted aquaculture experts to intensify their search for a suitable and sustainable alternative for aquafeed production. Based on this reality, the current study was designed to evaluate the dietary influence of African palm weevil oil (PWO) on the growth performance, serum biochemistry, lipid peroxidation products, antioxidant enzyme response, and organ integrity of African catfish (Clarias gariepinus) juveniles. Four diets were formulated, wherein the control diet was prepared using soybean oil (SO) as the main dietary oil source and was replaced with PWO in the treatment diets at 50% (PWO‐50), 75% (PWO‐75), or 100% (PWO‐100). A total of 180 African catfish (average weight: 18.76 ± 0.043) were randomly stocked at 15 fish per 50‐L tank in triplicate and hand‐fed to apparent satiation twice daily for 45 days. The results showed that the highest weight gain (WG), specific growth rate (SGR), and thermal growth coefficient (TGC) were found in control (SO)‐fed fish, which is similar to the PWO 50% but differs significantly from others (p < 0.05). The feed conversion ratio (FCR) and protein productive value (PPV) showed linear and quadratic trends, with a significantly lowest and highest value recorded in fish‐fed control and PWO 50%, respectively, compared to other dietary groups (p < 0.05). The protein efficiency ratio (PER) value decreases linearly (p < 0.001) as the level of PWO increases. The highest total immunoglobulin (TIG) and superoxide dismutase (SOD) activity were recorded in fish fed PWO‐50%, while PWO‐75% registered the highest lysozyme activity (LA). There was no statistically significant difference (p > 0.05) in the physiological parameters such as total cholesterol (TC), triglyceride (TG), low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), alanine aminotransferase (ALT), C‐reactive protein (CRP), and lipid peroxidation index (malondialdehyde [MDA]) among the groups. The fish fed PWO‐100% had the lowest recorded values of villus height, area of absorption, and cryptal depth (p < 0.05). In summary, the current finding shows that oil extracted from African palm weevils appears promising at a 50% dietary level without impairing the growth performance, liver, or intestinal health of African catfish. [ABSTRACT FROM AUTHOR]