Growth, plasma biochemical parameters, fish composition, immune parameters, intestinal histology, and expressions of immune-related genes were examined in hybrid grouper (Epinephelus lanceolatus ♂ × Epinephelus fuscoguttatus ♀) that fed respectively six diets containing Panax notoginseng extract (PNE) at 0, 0.5, 1, 2, 4, and 10 g kg−1 after 8 weeks. Results indicated that dietary PNE significantly improved growth, feed efficiency ratio, protein efficiency ratio, and protein deposit rate, and significantly increased crude protein and crude lipid levels of whole body and crude protein level of muscle. Dietary PNE significantly increased plasma total protein, alkaline phosphatase, immunoglobulin, complement 3 and complement 4 contents, but significantly decreased cholesterol, triglyceride, glucose, and low density lipoprotein cholesterol contents. Furthermore, dietary PNE increased villus length and muscle thickness in foregut, midgut, and hindgut, activities of hepatic superoxide dismutase and total antioxidant capacity, and increased the expression levels of immune related genes (IL-10, TGF-β1, TOR, MHC2 and TLR3) in the head kidney and the expression levels of antioxidant genes (CAT and GR) in fish that fed PNE at 0.5–4 g kg−1. In conclusion, grouper fed high lipid diets supplemented with PNE at 0.5–10 g kg−1 improved growth, feed utilization, blood immune parameters, hepatic antioxidant status, intestine morphology and expression levels of immune related genes in the head kidney.