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Introduction: Jabuticaba is a fruit rich in polyphenols with antioxidant activity. Fermentation can enhance the bioavailability of phenolic compounds, thereby potentiating their biological effects. This study investigated the antioxidant activity of polyphenol-rich extracts from fermented beverages of two jabuticaba species, Plinia peruviana and Plinia coronata, against ex vivo- and in vivo-induced oxidative stress. Methods: The phenolics (total, O-diphenols, and flavonoids) and antioxidant capacity (FRAP and ABTS assays) of the extracts were assessed. Hemolytic potential and influence on erythrocyte osmotic fragility were evaluated by the spectrophotometric detection of hemoglobin in the supernatant. To evaluate oxidative stress, the erythrocytes were pretreated with different concentrations of extracts and challenged with 7 mM AAPH (up to 4 h). Hamsters were pretreated with extracts (150 mg/kg/10 days) and challenged with nicotine (1 mg/mL) (approval registration: CEUA-UFRJ 089/21). Plasma antioxidant capacity was determined by FRAP. Biochemical markers (creatinine, urea, and uric acid) were measured using commercial kits. Liver and cardiac tissue samples were collected and evaluated by light microscopy. Results: PPE (P. peruviana extract) showed the highest levels of phenolics (108 mg GAE/g), O-diphenols (58 mg CE/g), and flavonoids (43 mg QE/g) and exhibited the highest antioxidant capacity (FRAP = 720 µmol Fe⁺²/g, ABTS = 3.05 mmol TE/g). Both extracts showed no hemolytic potential (HC50 > 500 µg/mL); instead, PPE showed a tendency to increase erythrocyte resistance to osmotic stress. Extracts provided maximum cellular protection against oxidative stress at the highest concentration (500 µg/mL). The in vivo assay demonstrated that the extracts protected animals against oxidative damage induced by nicotine similarly to the control (treated with silymarin, 150 mg/kg/10 days). A trend towards reduction in the serum levels of creatinine and uric acid was observed in animals pretreated and challenged with nicotine compared to the controls. Conclusion: The results suggest that fermented jabuticaba extracts are a rich source of antioxidants and could be potential candidates for nutraceutical formulations combating oxidative stress.