Opioid abuse is a serious problem in the society. Since the first months of COVID-19 pandemic, several myths, rumors and misconceptions have been spread about the benefits of opium consumption for COVID-19 outcome. In addition, data are limited on the relationship between opium abuse and COVID-19 mortality amongst hospitalized COVID-19 patients. In this historical cohort study, we assessed the risks of several variables for mortality amongst all hospitalized COVID-19 patients from the beginning of COVID-19 pandemic in South of Iran from March 15th, 2021 to October 14th, 2021. Data was acquired from the Medical Care Monitoring Center (MCMC), affiliated to Shiraz University of Medical Sciences. A total of 64,427 hospitalized COVID-19 patients were included into the analysis. The mortality rate was 10.59% (n = 6756). Of all, 2030 (3.15%) patients—1702 males and 328 females—reported the positive history of opium abuse with a mean age of 57 ± 17.21 years. The results of multivariable risk showed that the positive history of opium abuse had a significant association with mortality (adjusted RR: 1.173; p = 0.007). Other significant predictive risk factors were male gender, elder ages, and comorbidities such as pulmonary diseases, cardiovascular disease, cancer, nephrological diseases, neurological diseases, and diabetes. However, being a health care worker and having thyroid gland diseases were protective factors amongst hospitalized COVID-19 patients (adjusted RR: 0.650 and 0.642; p = 0.040 and < .0001, respectively). Opium abuse is a risk factor for mortality amongst hospitalized COVID-19 patients. It is vital to educate societies about the consequences of unauthorized opium consumption.