Contaminated surfaces and indoor environments are important sources of infectious spread within hospital and non-hospital facilities. Bacterial infections such as infections with Clostridioides (formerly Clostridium) difficile (C. difficile) and Staphylococcus aureus (S. aureus) and its antibiotic resistant strains continue to pose a significant risk to healthcare workers and patients. Additionally, the recent emergence of the coronavirus disease 2019 (COVID-19) pandemic, which is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), highlights the need for safe and effective methods to decontaminate surfaces to control infection spread in hospitals and the community. To address these critical needs, we tested a photocatalytic reactor decontamination method to disinfect contaminated surfaces in a hospital and a laboratory setting. By placing the reactor in a test hospital room, growth of S. aureus and C. difficile were significantly reduced compared with a control room. Additionally, using a model enveloped positive-sense single-stranded RNA virus, dengue virus type 2 (DENV2), we showed that the use of the photocatalytic reactor reduces viral infectivity. Collectively, the results demonstrate the potential utility of photocatalytic reactors in reducing the spread of highly contagious bacterial and viral infections through contaminated surfaces and environments.