Crude oil released into the environment undergoes weathering processes that gradually change its composition and toxicity. Co-exposure to petroleum mixtures and other stressors, including ultraviolet (UV) radiation, may lead to synergistic effects and increased toxicity. Laboratory studies should consider these factors when testing the effects of oil exposure on aquatic organisms. Here, we study transcriptomic responses of the estuarine sea anemone Nematostella vectensis to naturally weathered oil, with or without co-exposure to environmental levels of UV radiation. We find that co-exposure greatly enhances the response. We use bioinformatic analyses to identify molecular pathways implicated in this response, which suggest phototoxicity and oxidative damage as mechanisms for the enhanced stress response. Nematostella's stress response shares similarities with the vertebrate oxidative stress response, implying deep conservation of certain stress pathways in animals. We show that exposure to weathered oil along with surface-level UV exposure has substantial physiological consequences in a model cnidarian.