Opioid abuse is widespread throughout the world. Aspiration pneumonia is a serious problem following opioid overdose and poisoning. This study aimed to evaluate the safety and effectiveness of antimicrobial management of opioid-overdose induced aspiration pneumonia in a referral poisoning management university hospital in Iran. Methods: In an observational cross-sectional study (September–March 2019), opioid poisoned patients diagnosed with aspiration pneumonia within a maximum of 48 h of their overdose were evaluated regarding several variables, including the level of consciousness on admission, drug regimen used for the treatment of aspiration pneumonia, and its appropriateness, and the correctness of the used antibiotics dose and the therapeutic outcome. Findings: During the study, 53 eligible patients were identified and included in the study. The most frequently abused opioids were methadone (60.4%) and opium (17%). “Ceftriaxone + Clindamycin” (54.7%) and “Meropenem + Vancomycin” (9.5%) were the most frequently administered regimens. Regarding treatment outcome, most cases (n = 36, 67.9%) were discharged with a stable and satisfying medical status, while 3.8% of the cases (n = 2) died. Conclusion: The use of antibiotics in the treatment of aspiration pneumonia in hospitalized patients with opioid overdose in our referral university hospital is associated with notable antibiotic regimen choice issues. The implementation of strategies for improving the pattern of antibiotic prescribing for these patients is necessary.