The COVID-19 pandemic has tremendously increased the production and sales of disinfectants. This study aimed to systematically review and analyze the efficacy and safety of chlorine dioxide as a disinfectant. The literature relating to the use of chlorine dioxide as a disinfectant was systematically reviewed in January 2021 using databases such as PubMed, Science Direct, and Google Scholar. Inclusion criteria were studies that investigated the use of chlorine dioxide to assess the efficacy, safety, and impact of chlorine dioxide as a disinfectant. Out of the 33 included studies, 14 studies focused on the disinfectant efficacy of chlorine dioxide, 8 studies expounded on the safety and toxicity in humans and animals, and 15 studies discussed the impact, such as water treatment disinfection using chlorine dioxide. Chlorine dioxide is a safe and effective disinfectant, even at concentrations as low as 20 to 30 mg/L. Moreover, the efficacy of chlorine dioxide is mostly independent of pH. Chlorine dioxide can be effectively used to disinfect drinking water without much alteration of palatability and can also be used to destroy pathogenic microbes, including viruses, bacteria, and fungi from vegetables and fruits. Our review confirms that chlorine dioxide is effective against the resistant Mycobacterium, H1N1, and other influenza viruses. Studies generally support the use of chlorine dioxide as a disinfectant. The concentration deemed safe for usage still needs to be determined on a case-by-case basis.