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SARS-CoV-2 has caused a global pandemic, resulting in over two million deaths and creating an urgent need for effective treatments. Severe COVID-19 is frequently complicated by respiratory failure and acute respiratory distress syndrome (ARDS), the primary drivers of mortality. Indole-3-Carbinol (I3C), a natural compound derived from Brassicaceae that acts as an inhibitor of HECT family E3 ubiquitin ligases, exhibits potent anti-SARS-CoV-2 activity and inhibits viral egress. However, its in vivo therapeutic efficacy against SARS-CoV-2-induced lung injury remains unproven. We evaluated the therapeutic efficacy of I3C in reducing the severity of SARS-CoV-2 infection and associated lung lesions using the Syrian golden hamster (Mesocricetus auratus) model, which recapitulates the acute lung injury observed in human COVID-19. Treatment with a non-toxic dose of I3C (2 mg) significantly ameliorated disease across all parameters, reducing weight loss, improving clinical symptom scores and reducing histopathological lung damage observed post-mortem. A significant reduction in pulmonary TNF-α levels accompanied this. These findings indicate that I3C mitigates COVID-19-related morbidity at clinically relevant, non-toxic doses. Given its dual antiviral and anti-inflammatory mechanisms, I3C represents a compelling therapeutic candidate for further clinical investigation.