The aim of the study is to investigate whether dietary Chlorella sorokiniana supplementation could improve growth performance, antioxidant status, and immune response of Oncorhynchus mykiss. Three isonitrogenous (47%) and isolipidic (16.5%) diets supplemented with 0% (Control), 5% (5% CS), and 10% C. sorokiniana meal (10% CS) were assigned to O. mykiss (three replicates per diet, 30 fish in each replicate, initial body weight 165.24 +/- 0.46 g). The results indicated that O. mykiss fed with 5% CS diet had an increased feeding rate (FR), specific growth rate (SGR), and weight gain rate (WGR) compared to the control (P < 0.05). Dietary 5% or 10% C. sorokiniana supplementation significantly increased activity levels of superoxide dismutase (SOD) in the liver and catalase (CAT) in the liver and head kidney. In addition, dietary supplementation with 10% C. sorokiniana also significantly increased activity level of glutathione peroxidase (GPX) and simultaneously decreased contents of malondialdehyde (MDA) in the liver and head kidney. Furthermore, fish fed with 5% CS or 10 CS diet demonstrated increased activity level of lysozyme (LYZ), higher content of immunoglobulin M (IgM), and upregulated transcriptional expression of tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), hepcidin (HEP), and nuclear factor kappa-B (NF-kappa B) in the head kidney. Based on fish growth performance, antioxidant capacity, and immune response, dietary supplementation of 5% C. sorokiniana was recommended.