Background Proton pump inhibitors (PPIs) increase the risk of pneumonia secondary to PPI-induced hypochlorhydria. We aim to investigate the association between PPI and disease severity in coronavirus disease 2019 (COVID-19)-positive patients and the risk of hospitalizations in Muscat, Oman. Methodology COVID-19-positive patients aged 18 years and above at the time of diagnosis were included in this retrospective observational study. The details of the patients were retrieved from the electronic health records of the Al Shifa Hospital Information Management System and Tarassud. The composite primary endpoint was COVID-19 admission to a government tertiary hospital ward or intensive care within 14 days of diagnosis. Results A total of 506 COVID-19-positive patients were identified during the specified period. The mean age was 44 ± 15 years. The majority of the patients were Omani, and a female preponderance was observed. Overall, 104 (20.4%) patients were current PPI users. Admission due to COVID-19 was significantly associated with the presence of comorbid conditions such as diabetes mellitus (p = 0.001), hypertension (p = 0.001), and chronic kidney disease (p < 0.001). However, current PPI use (p = 0.140) was not significantly associated with an increased risk of hospitalization. Conclusions This data suggests that the use of PPIs during COVID-19 infection did not increase the risk of severe COVID-19 infection and poor outcomes leading to hospitalization in Muscat, Oman. However, the presence of other medical comorbidities, such as diabetes and hypertension, was associated with a higher risk of adverse clinical symptoms that resulted in hospitalization.