The COVID-19 pandemic has underscored the critical need for effective public health strategies to combat infectious diseases. This study examines the epidemiological characteristics and spatial distribution of COVID-19 incidence and mortality in Zanjan Province, northwest Iran, to inform future epidemic preparedness. Using data from 39,739 hospitalized COVID-19 cases recorded between February 2020 and September 2021, sourced from the Medical Care Monitoring Center, we conducted descriptive and geospatial analyses. Demographic, clinical, and spatial variables were analyzed using logistic regression and advanced spatial techniques, including Kernel Density Estimation and Local Moran’s I, to identify risk factors and disease hotspots. Results revealed that women accounted for 52% of cases, with higher incidence rates, while men exhibited higher mortality rates (7.86% vs. 7.80%). Urban areas, particularly the provincial capital, were identified as hotspots, with the highest patient density (20,384 cases per 10 km²). Comorbidities such as HIV/AIDS (OR: 4.85), chronic liver disease (OR: 3.6), chronic blood diseases (OR: 2.8), and cancer (OR: 2.5) significantly increased mortality risk, with ventilator use showing the highest odds ratio for death (OR = 91). Vaccination significantly reduced mortality, with fully vaccinated individuals experiencing a 6.3% mortality rate compared to 8.1% in unvaccinated individuals. Spatial analysis highlighted population density and mobility as key drivers of disease spread. These findings emphasize the importance of integrating spatial and epidemiological data to enhance pandemic preparedness. Targeted interventions in urban hotspots, early detection systems, and prioritizing vaccination for high-risk populations are critical for mitigating future outbreaks. This study provides a foundation for evidence-based public health strategies to strengthen global epidemic response and improve preparedness for future health crises.