The aim of this study was to investigate the effect of dietary supplementation of nanosize zinc on zinc digestibility, growth performances, immune response and serum parameters of weanling piglets. Ninety-six LYD weanling piglets were assigned to control, zinc oxide (ZnO), organic-Zn (Zn-methionine) and nanosize ZnO (nano-Zn) groups with four replicates. The zinc was at the 120 mg/kg level in the treatment group's diet, while the control group's was 80 mg/kg Zn. The experiment results indicated that the nano-Zn and organic-Zn groups had significantly higher Zn digestibility compared to the ZnO and control groups. For the immune response traits, the IgG level and goat red blood cells (GRBC) antibody titer were nano-Zn and organic-Zn>ZnO>control; in the phytohemagglutinin (PHA) challenge test result, nano-Zn>organic-Zn>ZnO>control; in regard to the γ-globulin level, nano-Zn and organic-Zn>ZnO and control, with significant difference between groups. In the serum parameters aspect, serum Zn concentration in nano-Zn and organic-Zn groups were higher than in the ZnO and control groups, serum growth hormone concentration was increased in the nano-Zn group than in the other groups. In conclusion, nanosize zinc oxide for dietary supplementation can increase zinc digestibility, serum growth hormone levels and carbonic anhydrase activity and enhance the immune response of weanling piglets.