Global climate change is predicted to increase the co-occurrence of high pCO₂ and hypoxia in 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 both 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 high pCO₂ and hypoxia, 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 major shift in cellular energetics indicates that blue rockfish may be relatively resistant to intensified upwelling conditions in the short term.