Plant-derived exosomes can exert therapeutic effects against various dermatological conditions. Several studies have demonstrated that plant-derived exosomes can have positive effects on the skin, preventing aging, hyperpigmentation, and hair loss. In this study, the protective effects of Iris germanica L. rhizome-derived exosomes (Iris-exosomes) on oxidative-stress-induced cellular dysfunction were investigated in human epidermal keratinocytes (nHEKs). Iris-exosomes with a diameter range of 100–300 nm were detected. In the cytotoxicity assay, Iris-exosomes with up to 10⁷ particles per milliliter were found to possess no cytotoxicity, and we recovered H₂O₂-induced cell viability loss. In nHEKs, H₂O₂-induced ROS levels were significantly reduced using Iris-exosomes and additionally associated with increases in antioxidant enzyme transcription. The H₂O₂-induced SA-β-gal-positive nHEKs were decreased using Iris-exosomes; these effects correlate with the changed levels of cell cycle arrest marker p21. Furthermore, the H₂O₂-induced loss of in vitro wound-healing properties and early detection of keratin 1 and 10—keratinization markers—were restored to control levels using Iris-exosomes. Altogether, these results indicate the possibility that Iris-exosomes exert antioxidant and anti-senescence effects in order to protect against oxidative-stress-induced cellular dysfunction in nHEKs.