Feed additives are edible ingredients that are very sparingly added to fish diets to improve the nutritional value of feed, which in turn enhances fish growth and health. Most recent research focused on their single use, but little is known about their combined application. Hence, a 7-week feeding trial was conducted to investigate the consequences of the dietary addition of papaya (Carica papaya) leaf powder (CPP) with or without alpha-lipoic acid (AL). The assessment encompassed the influence on growth, digestive capacity, body composition, physiological and antioxidant response, as well as disease resistance (Aeromonas hydrophila challenge). Five treatments containing 225 fish (N = 45 fish/group, 3 polyethylene cages /group, 15 fish/cage) with an average weight of 6.65 ± 1.85 g were haphazardly assigned. For 7 weeks, fish received basal diet supplemented with CPP alone or with AL [0 % (control), 2 %CPP (CPP2), 3 %CPP (CPP3), 2 % CPP with 0.1 %AL (CPP2 + AL0.1), and 3 %CPP with 0.1 %AL (CPP3 + AL0.1)]. Results displayed that CPP alone or with AL-fortified diets substantially boosted growth performance and digestive enzyme activity (amylase, lipase, and trypsin). Dietary CPP alone or with AL notably increased body lipid content, serum total protein, and hepatic antioxidant (reduced glutathione, superoxide dismutase, and total antioxidant capacity) parameters. Moreover, blood glucose and hepatic malondialdehyde showed lower values in the CPP alone or with AL diets. Surprisingly, the combination groups especially the CPP2 + AL0.1 group achieved the best results (P < 0.05) for these variables. Fifteen days postchallenge with A. hydrophila, the cumulative mortality declined among fish fed CPP alone or with AL diets, where the CPP2 + AL0.1 group did not record any mortality. Overall, the dietary intervention of CPP (2 %) with LA (0.1 %) by their synergistic potential can promote disease resistance, physiological-antioxidant status, growth, and digestive capacity of Nile tilapia. These advantageous outcomes can support the development of sustainable aquaculture.