This experiment was conducted to investigate the effect of the supplementation of hot-melt extrusion (HME) processed zinc sulfate (ZnSO) on the growth performance, antioxidative activity, pancreatic digestive enzyme, small intestinal morphology, nutrient digestibility, and Zn content in broilers. The chicks were allocated to three treatments, each of which had five replicates of 15 chicks per replicate. The broiler chickens were assigned to three dietary treatments: the control (without supplemental Zn), IN-Zn (ZnSO, 80 mg/kg), and HME-Zn (HME processed ZnSO as nano-Zn, 80 mg/kg). The broilers fed diets supplemented with 80 mg/kg of HME-Zn improved the BWG (P < 0.05) and FCR (P < 0.05) compared to the broilers fed the control and IN-Zn diets in phase 2. The Zn supplementation significantly enhanced the superoxide dismutase (SOD) activity in the serum (P < 0.05) and liver (P < 0.05), and HME-Zn supplementation significantly increased the SOD in the liver compared to the IN-Zn supplementation. Reduced malondialdehyde (MDA) concentration was seen with the Zn supplementation compared to the control (P < 0.05). The chickens fed diets supplemented with the HME-Zn had higher activity of amylase (P < 0.05) and trypsin (P < 0.05) than those of the chickens fed the control and IN-Zn diets. The villus height (VH) in the duodenum (P < 0.05) and jejunum (P < 0.05) increased with the ZnSO and HME-Zn supplementation compared to the control. The VH and crypt depth rate (VH:CD) in the jejunum improved with the HME-Zn compared to the control (P < 0.05). The HME-Zn significantly increased the apparent ileal digestible crude protein (CP) (P < 0.05) and energy corrected by nitrogen (AIDEn) (P < 0.05) compared to the control or IN-Zn. In phases 1 and 2, the HME-Zn significantly increased Zn concentration in the liver and tibia compared to control and IN-Zn (P < 0.05). The excretion of Zn was significantly decreased in the HME-Zn compared to the IN-Zn (P < 0.05). In conclusion, supplementation of 80 mg/kg of HME-Zn in diets improved the growth performance, antioxidative activity, pancreatic enzyme activity, intestinal villus height, and nutrient digestibility with the improved Zn bioavailability in broilers.