Alveolar hypoxia is protective in the context of ischemic heart disease; however, the relationship between hypoxia and the cardiac adaptation to pressure overload (PO) hypertrophy is currently not known. To test the hypothesis that alveolar hypoxia attenuates PO-induced heart failure following transverse aortic constriction (TAC), we established a novel murine model of combined chronic alveolar hypoxia and PO (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure as determined by transthoracic echocardiography, invasive measurement of left ventricular hemodynamics, stereological quantification of left ventricular tissue sections, and mRNA expression of heart failure markers. The cardioprotective mechanisms identified in our HxTAC model include increased activation of hypoxia-inducible factor (HIF)-1α-mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, we detected a decrease in Tbx5 and increase in Hsd11b1 mRNA expression post-TAC under normoxic conditions, which was attenuated under hypoxic conditions and thus might mediate additional hypoxia-mediated cardioprotective effects. Together, these data identify that alveolar hypoxia attenuates PO-induced heart failure and highlight the potential of our novel HxTAC model as a discovery tool to identify hypoxia-mediated cardioprotective mechanisms in the context of PO.