Cathelicidins are diverse effector molecules in the vertebrate immune system and are related to immune regulation, inflammatory response, wound healing, and blood vessel formation. However, little is known about their free radical scavenging ability, especially in vivo. In this study, a cathelicidin molecule (cathelicidin-NV, ARGKKECKDDRCRLLMKRGSFSYV) previously identified from the spot-bellied plateau frog (Nanorana ventripunctata) (Anura, Dicroglossidae, Dicroglossinae) by us was shown to alleviate ultraviolet B (UVB)-induced skin photoaging in mice. Cathelicidin-NV effectively suppressed cytotoxicity, DNA fragmentation, apoptosis and reduced the protein expression levels of JNK, c-Jun, and MMP-1, which are involved in the regulation of collagen degradation in HaCaT cells induced by UVB irradiation. Furthermore, cathelicidin-NV also scavenged UVB-induced intracellular reactive oxygen species (ROS). Taken together, cathelicidin-NV directly scavenged excessive intracellular ROS to protect HaCaT cells, and subsequently alleviated UVB-induced skin photoaging. This study extends reports on the antioxidant function of the cathelicidin family. In addition, the properties of cathelicidin-NV make it an excellent candidate for the prevention and treatment of UV-induced skin photoaging.