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Nile tilapia, a widely cultivated freshwater fish, faces significant stressors, such as hypoxia and cold temperatures, which can negatively impact its quality and growth. The current study explored the impact of Chlorella vulgaris (CV) powder and its nanoparticles (CVNPs) on the growth performance, antioxidant capacity, liver protection, and meat quality of Nile tilapia to alleviate hypoxia and cold stress. A total of 450 healthy 28-day-old Nile tilapia fingerlings (average weight 5.32 ± 1.1 g, length 3.1 ± 0.5 cm) were divided into five groups: T1 (2.5 g/kg CV), T2 (5 g/kg CV), T3 (2.5 g/kg CVNP), T4 (5 g/kg CVNP), and the control group received a basal diet without additives, each with three subgroups in tri-replicate (10 fish/replicate). After six weeks of feeding, growth metrics and meat quality parameters were assessed, and each group was subjected to hypoxia, cold stress, or optimal conditions. The results revealed that T4 exhibited the highest weight gain (WG) and lowest feed conversion ratio (FCR), whereas T1 showed the highest specific growth rate (SGR) and length gain. Hypoxia and cold stress significantly (p < 0.05) increased cortisol, oxidative markers (MDA, NO, and GSSG), and liver enzymes (ALT and AST) while reducing (p < 0.05) antioxidant markers (SOD and GSH) and total cholesterol (TC). ATP levels significantly (p < 0.05) decreased in hypoxic fish, indicating muscle energy depletion. T1 significantly (p < 0.05) lowered cortisol levels, whereas T2 and T3 significantly (p < 0.05) increased superoxide dismutase (SOD) levels. T2 also significantly (p < 0.05) increased the TC level. ALT levels significantly (p < 0.05) decreased at T1, T2, and T4, with AST levels reduced at T4 only. CV and CVNP supplementation significantly (p < 0.05) reduced the muscle MDA levels under optimal and stressful conditions, notably at T1 and T4. Additionally, meat lightness, yellowness, and chroma significantly (p < 0.05) increased in stressed tilapia, whereas meat redness was improved under optimal conditions. Fatty acid profiles varied with CV and CVNP levels across different conditions. In conclusion, CV, particularly in the nanoparticle form, enhanced the growth, antioxidant activity, and meat quality of tilapia under physical stress. [ABSTRACT FROM AUTHOR]