Zinc oxide (ZnO) nanoparticles (NPs) are widely used in cosmetics and sunscreen. In spite of the broad application of ZnO NPs on human skin, there are limited literatures on the potential toxicities of ZnO NPs at the cellular and molecular levels. The aim of this study was to investigate the signaling pathways of ZnO NPs-induced early growth response-1 (Egr-1) expression and the role of Egr-1 in ZnO NPs-induced cytokine expression. ZnO NPs increased the Egr-1 expression, promoter activity and its nuclear translocation in HaCaT cells. ZnO NPs activated extracellular signal-regulated kinase (ERK) of mitogen-activated protein kinase (MAPK) pathways. Up-regulation of Egr-1 expression by ZnO NPs stimulation was found to be inhibited by an ERK inhibitor, but by neither c-Jun-N-terminal kinase (JNK) nor p38 inhibitor. Our results showed that ZnO NPs induces Egr-1 expression via MAPK pathway in human keratinocytes and cytokine expression by Egr-1. These pathways may contribute to NPs-induced cutaneous toxicity.