Ocean acidification is hypothesized to limit the performance of squid owing to their exceptional oxygen demand and pH sensitivity of blood–oxygen binding, which may reduce oxygen supply in acidified waters. The critical oxygen partial pressure (Pcrit), the PO2 below which oxygen supply cannot match basal demand, is a commonly reported index of hypoxia tolerance. Any CO2-induced reduction in oxygen supply should be apparent as an increase in Pcrit. In this study, we assessed the effects of CO2 (46–143 Pa; 455–1410 μatm) on the metabolic rate and Pcrit of two squid species – Dosidicus gigas and Doryteuthis pealeii – through manipulative experiments. We also developed a model, with inputs for hemocyanin pH sensitivity, blood PCO2 and buffering capacity, that simulates blood oxygen supply under varying seawater CO2 partial pressures. We compare model outputs with measured Pcrit in squid. Using blood–O2 parameters from the literature for model inputs, we estimated that, in the absence of blood acid–base regulation, an increase in seawater PCO2 to 100 Pa (≈1000 μatm) would result in a maximum drop in arterial hemocyanin–O2 saturation by 1.6% at normoxia and a Pcrit increase of ≈0.5 kPa. Our live-animal experiments support this supposition, as CO2 had no effect on measured metabolic rate or Pcrit in either squid species.