Objectives: To systematically review the effectiveness and safety of chlorine dioxide solution and chlorine derivatives used in the prevention or treatment of COVID-19. Methods: This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) and follows the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions. A librarian developed and executed the search strategy; it was further reviewed by two of the authors and complemented by manual search. Randomized clinical trials, quasi-experimental studies, cohort studies, case-control studies, cross-sectional studies, and case reports were included; in vitro or animal studies were excluded. Abstract and full-text screening according to pre-defined eligibility criteria were performed by two reviewers independently using web application Rayyan QCRI. Disagreements on study selection were resolved by a third reviewer. The systematic review protocol was registered in PROSPERO (CRD42020200641). Results: Neither published nor pre-print studies evaluating the use of chlorine dioxide or derivatives on SARS-CoV-2 infection were identified. The only finding was an unpublished observational study registry which has no results released yet. Conclusions: To date, there are no scientific evidence to uphold the use of chlorine dioxide or derivatives as preventive or therapeutic agents against COVID-19.