KIOM-4 is a plant extract obtained from Magnolia officinalis, Pueraria Iobata, Glycyrrhiza uralensis, and Euphorbia pekinensis. Previously, we reported that KIOM-4 protects pancreatic $eta$-cells against streptozotocin (STZ) induced oxidative stress. To elucidate the cytoprotective mechanism of KIOM-4 on oxidative stress, we focused on the induction of heme oxygenase-1 (HO-1), which plays a role in cytoprotection against oxidative injury as well as providing an important function in the maintenance of homeostasis, in rat pancreatic $eta$-cells (RINm5F). In this study, we showed that KIOM-4 up-regulated HO-1 expression at the mRNA and protein levels, thus resulting in increased HO-1 activity. HO-1 induction is regulated at the transcriptional level and is mediated by a specific enhancer, the antioxidant response element (ARE), which is found in the promoter of HO-1 gene. The transcription factor, NF-E2 related factor 2 (Nrf2), interacts with the ARE to activate HO-1 gene transcription and results in the modulation of HO-1 expression. KIOM-4 increased the nuclear translocation, ARE binding, and transcriptional activity of Nrf2. In addition, the extracellular regulated kinase (ERK) positively contributed to ARE-driven HO-1 expression. Furthermore, KIOM-4 elicited the activation of ERK and U0126 (inhibitor of ERK) attenuated the KIOM-4 induced activation of Nrf2, which subsequently decreased HO-1 protein levels. These findings suggest that the induction of HO-1 by KIOM-4 is dependent on the ERK pathway. Taken together, KIOM-4 enhances the cellular antioxidant defense system through the induction of HO-1 via the ERK-Nrf2-ARE signaling pathway, thereby protecting cells from streptozotocin-induced cell damage.