Background: COVID-19 pandemic has had a devastating impact on global health, causing significant mortality and morbidity. Cancer patients are particularly vulnerable to the virus, with increased risks of adverse outcomes. In an effort to understand the factors that contribute to these outcomes, our study analyzed the predictors of mortality in cancer patients who were hospitalized for COVID-19 in the United States. Methods: In this retrospective cohort study, we used the National Inpatient Sample database 2020, the largest inpatient database in the United States, to analyze adult patients (≥18 years) who were hospitalized for COVID-19 and had a cancer diagnosis, as determined by ICD-10-CM codes. The primary outcome was in-hospital mortality. Secondary outcomes included acute respiratory failure (ARF), the need for mechanical ventilation (MV), length of stay (LOS), and total charges (TC). To identify predictors of in-hospital mortality, we performed a multivariable logistic regression analysis. A sensitivity analysis was also conducted based on the type of cancer. Results were considered statistically significant if the p-value < 0.05. Statistical analysis was conducted using STATA 17.0. Results: A total of 28,300 adult patients with cancer who were hospitalized for COVID-19 were included. The mean age was 71 years, with 56.8% being male and 63.6% being White. The most prevalent comorbidities were hypertension (70.1%), hyperlipidemia (44.5%), and diabetes mellitus (34.5%). The overall in-hospital mortality rate was 17.4%. About 56.9% of the patients experienced ARF and 10.1% required MV. The mean LOS and TC were 8.1 ± 8.7 days and $82,731 ± 152,297, respectively. Multivariable logistic regression analysis revealed that predictors of in-hospital mortality were age (odds ratio [OR] 1.04, 95%CI 1.03-1.05, p-value < 0.001), male gender (OR 1.18, 95%CI 1.01-1.37, p-value 0.03), congestive heart failure (OR 1.35, 95%CI 1.12-1.63, p-value < 0.001), chronic kidney disease (OR 1.46, 95%CI 1.21-1.76, p-value < 0.001), liver disease (OR 2.41, 95%CI 1.8-3.24, p-value < 0.001), and diabetes mellitus (OR 1.22, 95%CI 1.04-1.43, p-value 0.01). No racial or socioeconomic disparities were found to be associated with in-hospital mortality. Sensitivity analysis according to cancer type showed that patients with lung cancer had the highest in-hospital mortality rate (OR 1.89, 95%CI 1.22-2.92, p-value 0.004). Conclusions: The results of our study indicate that age, male gender, and the presence of certain comorbidities such as congestive heart failure, chronic kidney disease, liver disease, and diabetes mellitus significantly impact in-hospital mortality among cancer patients hospitalized for COVID-19. Notably, lung cancer patients experienced the worst outcomes. These findings provide valuable insights for clinical decision making and future research on COVID-19 in cancer patients.