Using a mouse equivalent of FDA-approved cannabidiol (CBD) dosing, we found high dose CBD affects opioid induced persistent apnea (OIPA), the principal cause of opioid related fatalities. CBD pretreatment mitigated respiratory depression from fentanyl in awake mice and significantly delayed OIPA onset in anesthetized mice, effective as the opioid antagonist naloxone. The powerful effect of CBD pretreatment on OIPA suggests a novel therapeutic strategy to reduce fatal opioid overdose incidence.