With the rapid development in nanotechnology, nickel nanoparticles (Ni NPs) have emerged in the application of nanomedicine in recent years. However, the potential adverse health effects of Ni NPs are unclear. In this study, we examined the inhibition effects of epigallocatechin-3-gallate (EGCG) on the toxicity induced by Ni NPs in mouse epidermal cell line (JB6 cell). MTT assay showed that Ni NPs induced cytotoxicity in a dose-dependent manner while EGCG exerted a certain inhibition on the toxicity. Additionally, EGCG could reduce the apoptotic cell number and the level of reactive oxygen species (ROS) in JB6 cells induced by Ni NPs. Furthermore, we observed that EGCG could down-regulate Ni NPs-induced activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) activation in JB6 cells, which has been shown to play pivotal roles in tumor initiation, promotion and progression. Western blot indicated that EGCG could alleviate the toxicity of Ni NPs through regulating protein changes in MAPK signaling pathways. In summary, our results suggest that careful evaluation on the potential health effects of Ni NPs is necessary before being widely used in the field of nanomedicine. Inhibition of EGCG on Ni NPs-induced cytotoxicity in JB6 cells may be through the MAPK signaling pathways suggesting that EGCG might be useful in preventing the toxicity of Ni NPs.