Background: The pandemic of COVID-19 has represented a major threat to global public health in the last century and therefore to identify predictors of mortality among COVID-19 hospitalized patients is widely justified. The aim of this study was to evaluate the possible usefulness of Charlson Comorbidity Index (CCI) as mortality predictor in patients hospitalized because COVID-19. Methods: This study was carried out in Zacatecas, Mexico, and it included 705 hospitalized patients with suspected of SARS-CoV-2 infection. Clinical data were collected, and the CCI score was calculated online using the calculator from the Sociedad Andaluza de Medicina Intensiva y Unidades Coronarias; the result was evaluated as mortality predictor among the patients with COVID-19. Results: 377 patients were positive for SARS-COV-2. Obesity increased the risk of intubation among the study population (odds ratio (OR) = 2.59; 95 CI: 1.36–4.92; p = 0.003). The CCI values were higher in patients who died because of COVID-19 complications than those observed in patients who survived (p < 0.001). Considering a CCI cutoff >31.69, the area under the ROC curve was 0.75, with a sensitivity and a specificity of 63.6% and 87.7%, respectively. Having a CCI value >31.69 increased the odds of death by 12.5 times among the study population (95% CI: 7.3–21.4; p < 0.001). Conclusions: The CCI is a suitable tool for the prediction of mortality in patients hospitalized for COVID-19. The presence of comorbidities in hospitalized patients with COVID-19 reflected as CCI > 31.69 increased the risk of death among the study population, so it is important to take precautionary measures in patients due to their condition and their increased vulnerability to SARS-CoV-2 infection.