Objective: This systematic review aimed to evaluate the antiviral effect of mouthwashes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Material and methods: An electronic search was performed on PubMed, Scopus, Web of Science, Cochrane Library, LILACS, ProQuest, and Google Scholar, and was complemented by a manual search. Both clinical and in vitro studies that focused on the antiviral effect of mouthwashes against SARS-CoV-2 were included. Risk of bias assessment was performed only on the clinical studies using the RoB-2 and ROBINS-I tools. Results: A total of 907 records were found; after initial selection by title and abstract, 33 full-text articles were selected to be evaluated for eligibility. Finally, a total of 27 studies were included for the qualitative synthesis, including 16 in vitro studies and 11 clinical trials. Antiviral effects were evaluated separately for the in vitro and clinical studies. In vitro studies included mouthwashes containing hydrogen peroxide, chlorhexidine digluconate, povidone-iodine, essential oils, cetylpyridinium chloride, and other compounds; in vivo studies included mouthwashes containing hydrogen peroxide, chlorhexidine digluconate, povidone-iodine, cetylpyridinium chloride, essential oils, chlorine dioxide, β-cyclodextrin-citrox, and sorbitol with xylitol. Povidone-iodine, cetylpyridinium chloride, and essential oils were effective in vitro, while hydrogen peroxide, chlorhexidine digluconate, povidone-iodine, cetylpyridinium chloride, β-cyclodextrin-citrox, and sorbitol with xylitol were effective in vivo. Unclear or high risk of bias was found for almost all clinical studies, and only one study presented with a low risk of bias. No further quantitative analysis was performed. Conclusion: Although povidone-iodine, cetylpyridinium chloride, and essential oils may be an alternative to reduce the viral load in vitro and in vivo, more studies are needed to determine the real antiviral effect of these different mouthwashes against SARS-CoV-2. This work was not funded. The protocol was registered in PROSPERO (identification number: CRD42021236134).