Zinc (Zn) deficiency is important for inducing nucleotide-binding domain and leucine-rich repeat-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in macrophages. However, its function in the NLRP3 inflammasome activation of peritoneal mesothelial cells (PMCs) remains to be elucidated. In the present study, the human PMC (HPMC) line HMrSV5 was co-treated with high glucose and either ZnSO4 or a Zn chelator. The activity of the NLRP3/caspase-1 inflammasome was assessed via western blot analysis, immunofluorescence, reverse transcription-quantitative polymerase chain reaction and ELISA. In addition, the activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was detected using western blotting, and the level of reactive oxygen species (ROS) was assessed by 2,7-dichlorofluorescein fluorescence and flow cytometry. It was found that Zn supplementation inhibited HG-induced NLRP3 inflammasome activation in the HPMCs by attenuating ROS production. Further experiments revealed that Zn supplementation inhibited the HG-induced production of ROS through activation of the Nrf2 antioxidant pathway. These results indicated that Zn inhibited NLRP3 inflammasome activation in the HG-treated HPMCs by activating the Nrf2 antioxidant pathway and reducing the production of ROS.