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. Highlights Chlorhexidine is a simple and safe addition to the current COVID‐19 prevention guidelines. When used with vaccination, proper social distancing, mask wearing, and hand hygiene, chlorhexidine may contribute to a more robust disease prevention regimen.