As public distribution of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is underway, prevention of coronavirus disease 2019 (COVID-19) relies on minimizing spread. In this study, chlorhexidine gluconate was investigated as a topical antimicrobial agent against SARS-CoV-2. This was a randomized, prospective cohort study using chlorhexidine as an oral rinse and posterior oropharyngeal spray in hospitalized COVID-19 patients. The primary outcome was presence or absence of laboratory-confirmed SARS-CoV-2 in the oral and oropharyngeal cavities after 4 days of chlorhexidine use and standard of care (study group) or standard of care only (control group). SARS-CoV-2 was eliminated from the oropharynx in 62.1% of patients who used chlorhexidine as an oral rinse, versus 5.5% of the control group patients. Among patients who used a combination of oral rinse and oropharyngeal spray, 86.0% eliminated oropharyngeal SARS-CoV-2, versus 6.3% of control patients. Chlorhexidine is a simple and safe addition to current COVID-19 prevention guidelines and may play a significant role in reducing disease spread.