The basal mass-specific O2 requirements of the smallest (2-4 g) endothermic mammals and birds are a remarkable 74 and 83 times higher respectively than those of an ~4 tonne elephant; accordingly, their tissues require higher rates of O2 delivery at rest than those of larger species during vigorous exercise. Molecular modifications to hemoglobin (Hb), such as a reduced O2 affinity and a high Bohr effect (reduction of Hb-O2 affinity induced by acidity), help small endotherms meet their high O2 requirements. Here I examine an additional though largely unexplored Hb specialization in small high metabolic rate endotherms, namely a reduced specific Hb buffer value (βHb) arising from reductions in titratable Hb histidine content. Previous work suggested that a low βHb may cause an exaggerated reduction in red blood cell pH for a given acid (CO2) load, which then through the Bohr effect would augment O2 offloading, though this has not been formally examined. I predicted that lineages of small endothermic birds and mammals, specifically those with elevated basal mass-specific metabolic rates, will have convergently evolved Hb proteins with significantly reduced βHb values to help them meet their high mass-specific O2 needs. To test this hypothesis, I calculated the predicted specific Hb buffer value (pβHb; which is shown to track measured βHb values) for 369 avian and 449 mammalian species using the site specific pKa’s of the imidazole side chains of solvent exposed histidines and the amino termini from the primary structures of their component globin chains. I then reconstructed the evolutionary history of pβHb for the avian and mammalian clades. I found significant reductions in pβHb in hummingbirds (47%), perching birds (39%), shrews (29%) and bats (18%), relative to the phylogenetic mean of their respective classes. My theoretical calculations accordingly demonstrate that these traits have a large positive impact on O2 delivery potential while safeguarding O2 uptake at the lungs. By fostering an elevated metabolic rate, this largely overlooked molecular adaptation (reduced βHb) of Hb—historically arguably the most intensively studied of all proteins—is presumably an important component underlying the evolutionary success of the small endotherm clades exhibiting this adaptation.