Skin exposure to UV rays causes the production of reactive oxygen species (ROS), and it is a major risk factor for various skin disorders and diseases. In particular, exposure to UV-A is a major cause of photoaging. We have previously isolated 2ʹ,3ʹ-dihydroxy-4ʹ,6ʹ-dimethoxychalcone (DDC) from green perilla leaves as an activator of the nuclear factor erythroid 2-related factor-2 (Nrf2)–antioxidant response element (ARE) and demonstrated the protective effects of DDC both in vitro and in vivo in PC12 cells and Parkinson’s disease models, respectively. In this study, we used HaCaT cells to examine the effects of DDC on ROS production and cell damage induced by UV-A. Our results indicated that UV-A irradiation in HaCaT cells increased ROS production in an energy-dependent manner. In addition, cell viability decreased in an energy-dependent manner 24 h after UV-A irradiation. However, treatment with DDC 24 h prior to UV-A irradiation significantly suppressed UV-A radiation-induced ROS production. In addition, DDC showed cytoprotective effects when used 24 h before and after UV-A irradiation. Treatment with DDC for 24 h also increased the expression levels of heme oxygenase-1 (HO-1) in a concentration-dependent manner. Pretreatment with the HO-1 inhibitor followed by DDC treatment before UV-A irradiation for 24 h reduced ROS production and the cytoprotective effect. These results suggest that DDC increases the expression levels of HO-1 and protects HaCaT cells through the suppression of UV radiation-induced ROS production.