The current work studied the influence of artichoke (Cynara scolymus) extract (AE) on growth, digestive enzymes, mucus immune status, liver antioxidant capacity, and health in Nile tilapia (Oreochromis niloticus). For that, Nile tilapia was allocated into four groups and fed for 56 days on 0 (group T0), 100 (group T1), 150 (group T2), and 200 (group T3) mg of AE/kg feed. After the growth trial, fish were exposed to a heat stress challenge (over heat) and immune response, antioxidant enzymes, and stress factors which were measured pre and post-heat stress. Growth, feed efficiency, and protease, trypsin, and amylase activ ities significantly increased in fish fed the AE-supplemented diets. All measured mucus immune- (excepting alternative complement activity, ACH50) and liver antioxidant- and health-related enzymes and stress factors were negatively affected by the heat stress chal lenge. Dietary AE supplementation led to an increase in mucus total immunoglobulin, lysozyme, and ACH50 before and after heat stress. Independently of the heat stress, cat alase and glutathione peroxidase (GPx) activities increased in fish fed diets T2 and T3, while malondialdehyde (MDA) content decreased. Liver alanine aminotransferase and aspartate aminotransferase (AST) activities, glucose, and cortisol content were decreased in fish fed AE-supplemented diets, both before and after heat stress. A significant interac tion between diets and heat stress was observed only in mucus lysozyme, liver MDA, GPx, and AST. Prior to being subjected to heat stress, the expression of IL-1b, lysozyme, GPx, and CAT exhibited significant upregulation compared to the fish fed control diet (p < 0.05). In conclusion, the use of AE in tilapia diets has the ability to boost growth performance, digestive and antioxidant enzymes activity, immune status, hepatic function, and mitigate stress in tissue prior and post-exposure to heat stress, and it can add to fish diet to achieve aquaculture sustainability and fish well-being.