A total of 180 Nile tilapia fingerlings (10 ± 0.5 g) were separated into three groups (n = 60), including a control group and two experimental groups supplemented with Spirulina platensis (SP; 5 g.kg-1) and curcumin nanoparticles (Cu-NPs; 30 mg.kg-1), respectively. After a 56-day feeding study, an evaluation of growth performance, hematological factors, antioxidant activity, biochemical and immunological characteristics, and histological modifications were conducted. The results revealed that the SP- and Cu-NPs supplements significantly improved growth indices, carcass features and biochemical features in both experimental groups compared to the control. Furthermore, the activities of digestive enzymes, comprising amylase, lipase, and protease, were significantly increased in the SP and Cu-NPs groups, unlike the control group. Additionally, supplementation with Cu-NPs and SP significantly enhanced the antioxidant state, as exhibited by increased glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity and decreased activity of malondialdehyde (MDA). The immune response was also significantly improved, with higher serum IgM and lysozyme activity in the SP and Cu-NPs treatments. Therefore, this study provides evidence that dietary supplementation with Cu-NPs and SP efficiently enhances the activity of digestive enzymes, antioxidant capacity, growth and performance, hepatoprotective capabilities, histopathology, and immune responses of Nile tilapia fingerlings.