INTRODUCTION: Intranasally (IN) administered antiviral therapies have emerged as a promising approach to combating SARS-CoV-2 respiratory tract infections. This systematic review aims to examine published preclinical animal studies that report anti-SARS-CoV-2 effects because of IN-delivered antiviral drugs between 1 December 2019 and 1 March 2025. METHODS: Our analysis revealed 36 relevant studies out of 792 identified studies. Importantly, 15 out of the 36 selected studies performed prophylactic and post-exposure IN treatments in preclinical animal models. RESULTS: Our systematic analysis revealed six classes of IN-delivered antiviral therapeutics that significantly improved in vivo survival and reduced target organ viremia with minimal side effects in mice. Antiviral interventions resulted in animal body weight recovery (27 studies), better clinical survival (14 studies) and reduced organ viral loads (infectious viral titers (13 studies) and RNA viral loads (27 studies)). Out of these, one study reported negative outcomes of IN interventions, significant weight loss (one study) and poorer mouse survival (two studies). CONCLUSIONS: Our systematic analysis revealed a moderate association between IN antiviral therapies and clinical and antiviral efficacy. Though the evidence supports the effectiveness of IN antiviral therapies in preclinical models, translation to clinical efficacy in humans remains uncertain. PROSPERO REGISTRATION: CRD42024492039.