The efficacy of marine protected areas (MPAs) may be reduced when climate change disrupts the ecosystems and human communities around which they are designed. The effects of ocean warming on MPA functioning have received attention but less is known about how multiple climatic stressors may influence MPAs efficacy. Using a novel dataset incorporating 8.8 million oceanographic observations, we assess exposure to potentially stressful temperatures, dissolved oxygen concentrations, and pH levels across the California MPA network. This dataset covers more than two-thirds of California’s 124 MPAs and multiple biogeographic domains. However, spatial-temporal and methodological patchiness constrains the extent to which systematic evaluation of exposure is possible across the network. Across a set of nine well-monitored MPAs, the most frequently observed combination of stressful conditions was hypoxic conditions (<140 umol/kg) co-occurring with low pH (<7.75). Conversely, MPAs exposed most frequently to anomalously warm conditions were less likely to experience hypoxia and low pH, although exposure to hypoxia varied throughout the 2014–2016 marine heatwaves. Finally, we found that the spatial patterns of exposure to hypoxia and low pH across the MPA network remained stable across years. This multiple stressor analysis both confirms and challenges prior hypotheses regarding MPA efficacy under global environmental change.