Levine‐prepared, female, Sprague‐Dawley rats were used to investigate the possible protective effects of the NMDA receptor‐blocker anesthetic ketamine and the Ca2+ channel‐blocker verapamil (0.4 mg kg−1 ‘low dose’, and 1.0 mg kg−1 ‘high dose’) in rats during acute 2400 ppm carbon monoxide (CO) poisoning. Blood glucose and lactate concentrations, heart rate, mean arterial blood pressure (BP), body temperature (BT), neurological function and cerebral cortical water content were measured. In most cases glucose increased after 45 min and then fell to initial values after 90 min. Lactate concentration increased sharply during CO exposure in the saline and in the low‐ and high‐dose verapamil groups, while the lactate increase in rats given ketamine at 40 mg kg−1 was significantly lower than with saline. Lactate was also significantly lower in these rats after 90 min than in the high‐dose verapamil group. Lactate was normal in all four groups after 2 and 4 h of air recovery. Ketamine significantly lowered the heart rate prior to CO exposure, and the heart rate remained significantly below values for the saline and for the low‐ and high‐dose verapamil groups throughout CO exposure. The BP decreased in all groups during CO exposure, and the BP recovery which took place in all four groups was significantly more rapid in the ketamine group. Recovery from CO‐induced hypothermia was similar in the ketamine and saline groups, whereas rewarming tended to occur more slowly and less completely in the two verapamil‐treated groups. There were no significant differences in neurological function among the four groups, as assessed after 4 h of recovery. However, cerebral edema was significantly reduced by treatment with 40 mg kg−1 ketamine as compared with saline. Verapamil at neither the low nor the high doses was of significant benefit in this regard. No rat in the 40 mg kg−1 ketamine group died during CO exposure, whereas all deaths in the other groups took place during CO exposure. The use of higher and lower doses of ketamine suggest 40–80 mg kg−1 as most effective in suppressing lactate production; 40 mg kg−1 ketamine may be optimal with regard to survival. The results suggest that ketamine is beneficial, when administered before and during acute severe CO poisoning, in reducing blood lactate and cerebral edema and in improving BP recovery and survival. Verapamil, in contrast, appears to provide no benefits in these respects.