The present study investigated influence of Yucca schidigera extract (Ys E) on the growth performance, hepato‐renal function, antioxidative status and histopathological alterations in Nile tilapia (Oreochromis niloticus) exposed to hypoxia stress. 120 Nile tilapia fish (42.39 ± 1.25 g) were distributed into four equal groups, where group (a) kept as a control group, group (b) supplied with YsE (8 mg/L water every 2 days), group (c) exposed to hypoxia after 2 weeks from the start of the experiment and group (d) provided with YsE for 2 weeks and then exposed to hypoxia. The treatments were conducted for 30 days. The results showed that the level of DO was significantly decreased (2.2 ± 0.61) in groups of fish exposed to hypoxia when compared to other groups (p < 0.05). Notably, the pre‐supplementation with YsE to hypoxic stressed fish positively affected the WG, SGR, FCR and PER, relieved stress picture of leukogram, reduced the elevated hepatic marker enzymes: ALT, AST and LDH. Furthermore, hypoxic fish pre‐treated with YsE succeeded to decline the increased urea, glucose levels and the elevated serum amlyase and lipase enzyme activities. In addition to improving total proteins, albumin, total cholesterol, triglycerides, VLDL‐C and HDL‐C declined levels compared to hypoxic fish. Meanwhile hypoxia‐stressed fish exhibited significantly enhanced hepatic GPX, SOD and GSH and inhibited hepatic MDA content compared to fish supplied with YsE then exposed to hypoxia. Fish group pre‐supplemented with YsE then exposed to hypoxic stress condition was protected against the pathological changes of the liver, spleen, brain and gills tissues induced by hypoxic stress condition. These results suggest that YsE could exert a beneficial effect against hypoxia‐induced oxidative stress.