Background: The outbreak of a new coronavirus in China in 2019 (COVID-19) caused a global health crisis. Objectives: This study was performed to investigate the effect of different underlying diseases on mortality in patients with COVID-19. Methods: This retrospective cohort study was performed on COVID-19 patients admitted to the Shahid Rahimi and Sohada-ye Ashayer teaching hospitals in Khorramabad, Iran, from 2019 to 2021. Data on disease severity, clinical manifestations, mortality, and underlying disorders were collected and analyzed using the SPSS software version 22 at a 95% confidence interval and 0.05 significance level. Results: The study included 9653 men (48%) and 10332 women (52%). Patients with chronic kidney diseases, cancer, chronic obstructive pulmonary disease, hypertension, cardiovascular disease, and diabetes were at higher mortality risk than those without these underlying diseases, respectively. However, there was no significant relationship between asthma and mortality. Also, age > 50 years, male gender, oxygen saturation < 93 on admission, and symptoms lasting ≤ 5 days were associated with increased mortality. Conclusions: Since patients with underlying diseases are at higher mortality risk, they should precisely follow the advice provided by health authorities and receive a complete COVID-19 vaccination series.