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Hypoxia and acidification frequently co-occur in coastal marine ecosystems, and will likely become more intense and persistent with anthropogenic climate change. Although the separate effects of these stressors have previously been described, their combined effects on marine phytoplankton are currently unknown. In this novel study, multi-stressor incubation experiments using the harmful dinoflagellate, Amphidinium carterae, examined the effects of acidification and hypoxia both individually and in combination. Long-term (7 days) and short-term (6 h) experiments under controlled carbon dioxide (CO2) and oxygen (O-2) conditions examined the interactive effects of the stressors and the physiological mechanisms driving their interaction. In the long-term experiment, synergistically negative effects were observed for A. carterae growth, photosynthesis, carbon fixation, nitrate uptake, and photosynthetic efficiency (F-v/F-m) under combined high CO2 (low pH) and low O-2 conditions. In the short-term experiment, delayed recovery of photosystem II (PSII) reaction centers was observed following photoinhibition, suggesting that high CO2 and low O-2 conditions negatively affect photosynthesis in A. carterae even after relatively short exposures. Although high CO2, low O-2 conditions should decrease photorespiration and favor carbon fixation by the key photosynthetic enzyme ribulose-1,5-bisphosphate-carboxylase/oxygenase (RuBisCO), these findings demonstrate that the affinity of RuBisCO for CO2 relative to O-2 alone does not predict phytoplankton responses to CO2 and O-2 conditions in vivo, complicating predictions of phytoplankton community responses to hypoxia and acidification. Results of these experiments suggest that the combination of low pH and O-2 concentrations may negatively impact the growth of some harmful dinoflagellates in coastal marine ecosystems.