Aquatic ecosystems are threatened by multiple stressors which might interact in non-additive ways. Two key stressors in marine systems that are likely to be mediated by ongoing climate change are temperature and salinity. Here, we experimentally examine the influence of warming and desalination on mortality rates of a key herbivorous sea urchin, Paracentrotus lividus, between two populations over time. Mortality rates were significantly increased by warming and desalination as individual stressors, with up to total mortality exhibited at the highest water temperature (27 °C) and lowest salinity (25). However, these stressors interacted, with desalination significantly exacerbating mortality rates at the highest temperature, but not under lower thermal regimes (21 °C and 25 °C). Mortality rates were relatively consistent between two sea urchin populations. Overall, temperature and salinity stressors can significantly interact to mediate mortality rates of key aquatic species, in ways that cannot be predicted by considering individual stressors in isolation. Future research should incorporate multiple environmental contexts to better understand and predict species responses to changing climate.