We examined the circulatory mechanisms underlying adaptive increases in thermogenic capacity in deer mice (Peromyscus maniculatus) native to the cold hypoxic environment at high altitudes. Deer mice from high- and low-altitude populations were born and raised in captivity to adulthood, and then acclimated to normoxia or hypobaric hypoxia (simulating hypoxia at ∼4300 m). Thermogenic capacity [maximal O2 consumption (V̇O2,max), during cold exposure] was measured in hypoxia, along with arterial O2 saturation (SaO2) and heart rate (fH). Hypoxia acclimation increased V̇O2,max by a greater magnitude in highlanders than in lowlanders. Highlanders also had higher SaO2 and extracted more O2 from the blood per heartbeat (O2 pulse=V̇O2,max/fH). Hypoxia acclimation increased fH, O2 pulse and capillary density in the left ventricle of the heart. Our results suggest that adaptive increases in thermogenic capacity involve integrated functional changes across the O2 cascade that augment O2 circulation and extraction from the blood.