A long-term feeding study was conducted to evaluate the effects of dietary supplementation with dried Siraitia grosvenorii fruit (SGF) on the growth performance, antioxidant status, hemolymph biochemistry, immune response, and resistance to Vibrio parahaemolyticus of Litopenaeus vannamei shrimp. Two hundred and forty healthy shrimp were randomly assigned to four experimental groups. Shrimp was fed a basal diet containing 0 (SGF0), 300 (SGF300), 450 (SGF450), or 600 (SGF600) mg of Siraitia grosvenorii fruit (SGF) per kilogram of feed for a 90-day feeding trial. The results demonstrated that dietary supplementation with SGF significantly enhanced growth performance and feed utilization (P < 0.05) in shrimp. Significantly higher levels of crude protein and lipid content were observed in the SGF-supplemented groups compared to the control group (P < 0.05). Shrimp in all SGF-supplemented groups exhibited significant enhancements in serum digestive enzyme activities (amylase, lipase, and protease; P < 0.001) and immunoglobulin levels (IgA and IgM; P < 0.001). Moreover, blood protein levels were significantly elevated in the SGF450 and SGF600 groups compared to the control group (P < 0.001). SGF supplementation significantly decreased liver enzyme activities (GGT, AST, LDH, and ALT), with the most pronounced reductions observed at the 450 and 600 mg/kg diet levels. All SGF groups significantly lowered the lipid profile, including total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) compared to diet-free SGF (P < 0.05). Dietary inclusion of 450 or 600 mg of SGF/kg diet significantly enhanced antioxidant parameters, such as total antioxidant capacity (TAC), glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) compared to SGF300 and control groups (P < 0.05). Conversely, all SGF-supplemented groups exhibited a significant decrease in malondialdehyde (MDA) levels. The expression of the growth hormone (GH) gene and antioxidant-related genes (catalase, cMnSOD, and GPx1) was significantly upregulated following SGF supplementation. The survival rate was higher in shrimp given SGF in their diets. In conclusion, dietary supplementation with SGF enhanced blood health and growth performance in shrimp by stimulating antioxidant gene expression and immune function. These findings suggest the potential of SGF as a promising growth promoter in shrimp aquaculture.