Global climate change is predicted to increase the co-occurrence of high pCO2 and hypoxia in coastal upwelling zones worldwide. Yet, few studies have examined the effects of these stressors on economically and ecologically important fishes. Here, we investigated short-term responses of juvenile blue rockfish (Sebastes mystinus) to independent and combined high pCO2 and hypoxia at the molecular level, using changes in gene expression and metabolic enzymatic activity to investigate potential shifts in energy metabolism. Fish were experimentally exposed to conditions associated with intensified upwelling under climate change: high pCO2 (1200 μatm, pH~7.6), hypoxia (4.0 mg O2/L), and a combined high pCO2/hypoxia treatment for 12 h, 24 h, or two weeks. Muscle transcriptome profiles varied significantly among the three treatments, with limited overlap among genes responsive to the single and combined stressors. Under elevated pCO2, blue rockfish increased expression of genes encoding proteins involved in the electron transport chain and muscle contraction. Under hypoxia, blue rockfish up-regulated genes involved in oxygen and ion transport and down-regulated transcriptional machinery. Under combined stressors, blue rockfish induced a unique set of ionoregulatory and hypoxia-responsive genes not expressed under the single stressors. Thus, high pCO2 and hypoxia exposure appears to induce a non-additive transcriptomic response that cannot be predicted from single stressor exposures alone, further highlighting the need for multiple stressor studies at the molecular level. Overall, lack of a shift towards anaerobic metabolism or induction of a cellular stress response under multiple stressors suggests that blue rockfish may be relatively resistant to intensified upwelling conditions in the short term.