Chlorella meal as feed ingredient in diets has been well evaluated in fish and shellfish, whereas limited information is available about Chlorella extract as feed supplement and their effects on growth performance and stress resistance of fish. This study was conducted to assess effect of Chlorella water extract (CWE) on growth performance, body composition, digestive enzyme activity, antioxidant and immune capacity, histomorphology, and sodium nitrite stress resistance of Oreochromis niloticus. In total of 1920 O. niloticus fingerlings with initial body weight of 0.9 ± 0.01 g were randomly distributed into six groups with four replicates (80 fish per replicate) and fed six diets containing 0 (C0), 2.7 (C2.7), 5.5 (C5.5), 11 (C11), 22 (C22), and 33 (C33) ml/kg dry matter of CWE for 56 d. Fish were suffered with a 24-h sodium nitrite stress test at the end of feeding trial. Results indicated that dietary CWE did not affect growth performance, body composition and histological appearance of fish, but quadratically increased (P < 0.05) protein efficiency ratio and trypsin activity as dietary CWE increasing. Inclusion of CWE in diets increased (P < 0.05) hepatic glutathione peroxidase and lysozyme activities. Fish fed CWE-containing diets had lower (P < 0.05) cumulative mortality rate but higher (P < 0.05) acid phosphatase and lysozyme activities as observed in the sodium nitrite stress test. In conclusion, dietary CWE did not affect growth performance, body composition and histological appearance, but improved protein utilization, trypsin activity, antioxidant and immune capacity, and sodium nitrite stress resistance of O. niloticus.