Epidermal growth factor (EGF) stimulates cell growth, proliferation, and survival. The biological benefits of EGF have been utilized in medical uses for improving wound healing as well as in today's skin cosmetics. EGF has been found in urine, saliva, milk, and plasma, but its efficient isolation remains a difficult task. With technical advances, recombinant protein purification technique has been used for EGF production. However, the recombinant EGF is still expensive and keeping it with stable activity is difficult to be used widely. Thus, a molecule that can mimic the EGF activity would be a useful alternative of EGF. Herein, we have discovered that a natural small molecule piperonylic acid shows EGF-like activity in HaCaT keratinocytes. Piperonylic acid induced EGF receptor (EGFR) activation and resulted in serial activation of the downstream modulators. The activated signaling pathway eventually up-regulated gene expression of egr-1, c-fos, c-jun, and c-myc, which are involved in cell growth and survival. Moreover, piperonylic acid showed promoting role in keratinocyte growth and survival from UVB-induced cellular damages. This study has revealed the EGF-like activity of piperonylic acid and proposed that the piperonylic acid could be a promising component for skin wound healing agents or cosmetic ingredient.