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Background Patients presenting to the emergency department (ED) following nonfatal opioid overdose represent a high-risk population with 5 % of patients dying within a year of the index visit. Objective To evaluate subsequent overdose and death before and after the implementation of an ED discharge naloxone program. Methods This was a retrospective cohort study of ED patients who presented at the Virginia Commonwealth University Health ED with an Opioid Use Disorder (OUD) chief complaint before and after a discharge naloxone program. The pre-naloxone cohort was consecutive ED OUD patients from August 15, 2021, to August 14, 2022, and the post-naloxone cohort from August 15, 2022, to August 14, 2023. The outcomes were subsequent overdose, ED visit to same hospital (VCU), and death within six months of the index visit. Results In total, 1,053 patients were included, of which 529 were in the pre-naloxone cohort and 524 patients in the post-naloxone cohort. The mean age was 44.2 years (SD = 14.0) and 69 % were males. There was a reduction in overdose requiring ED visiting (subsequent ED overdose) and death (4.6 % vs 9.2 % p = 0.03 and 2.0 % vs 5.6 % p = 0.02 respectively) in the post-naloxone cohort compared to the pre-naloxone cohort. After adjusting for sociodemographic and clinical factors, there was a 48 % reduction in the risk of subsequent ED overdose (RR = 0.52, 95 % CI: 0.27, 1.02) and a 63 % reduction in the risk of death (RR = 0.37, 95 % CI: 0.14, 0.95). Conclusion Implementing an ED take-home naloxone program was associated with a reduction in subsequent overdose and death at six months.