Since the COVID-19 pandemic originated in Wuhan, China in early December 2019, millions of lives have been lost. In an epidemic, it is necessary to explore the number of infections and deaths, identify the populations at risk, and determine the factors influencing disease death. The Retrospective cohort study used of 2110 hospitalized patients with COVID-19 data recorded in the Medical Care Monitoring Center information system from March 1, 2020, to February 7, 2021, in the city of Rafsanjan. Among a total of 2110 hospitalized patients (mean age: 56.11, SD: 19.37 years), there were 1125 (54.2%) females, 228 (10.8%) readmissions, and 318 (15.1%) deaths. The highest percentage (70.2%) of hospitalized patients with COVID-19 was infected during the third and early fourth waves. Mortality was high in elderly patients, males, patients with underlying diseases, and those who received mechanical ventilation. The in-hospital mortality trend decreased from the first (19.2%) to the second wave (10.7%) and increased significantly during the third and early fourth waves (16.3%) (P < 0.01).The median 43-day in-hospital survival time was 17 days. An adjusted Multivariable logistic regression showed the age as a strong risk factor for deaths due to COVID-19 while also indicating in both age sub-group analyses that cancer, CKD, neurologic disease, opium, and diabetes were associated with increased odds of death. Finally, patients aged ≥ 65 with CVD and COPD and patients aged < 65 with hypertension were associated with increased odds of death. The area under the ROC curve was 0.809 (95% CI: 0.76–0.83, P < 0.001) to discriminate between discharge and death on hospitalized patients with COVID-19. Our study showed that the effect of the pre-existing chronic diseases on the mortality of COVID-19 varied by age, Also opium was an independent risk factor for in-hospital mortality of COVID-19.