Background: Astilbin is a flavonoid phytoconstituent extracted from Chinese herb Rhizoma Smilacis Glabrae, a common Chinese food ingredient. Objectives: The present study used astilbin as a model drug to develop food-based nanoemulsified formulations. These formulations were then tested for their possible role in countering Oxaliplatin (OXP) associated oxidative stress. Materials and Methods: Thirty six healthy male BALB/c mice of age 10–12 weeks and weight 25–30 g were included in the present study. The mice were administered OXP through intraperitoneal route in a dose of 8 mg/kg for a period of 4 days. The animals in the control group were administered a 10 ml/kg dose of 5% (w/v) glucose solution. For evaluating the hepatoprotective effect of developed formulations on OXP-induced liver injury, the animals from treatment groups were administered once daily dose of drug loaded formulations 60 min before OXP treatments (200 mg/kg equivalent of formulation, intraperitoneally) for 4 days. Finally, the blood and hepatic tissue samples were obtained for future analysis. Results: We successfully developed non-toxic nanoemulsion systems for astilbin, which comprised of different non-toxic food ingredients of astilbin and evaluated the potential reversing the OXP induced liver injury. The food-based nanoemulsions possessed attractive physical properties and exhibited sufficient stability profile when subjected to freeze-thaw cycles as well as 6-month storage at ambient and cold temperatures. Furthermore, excellent cumulative in vitro drug permeation was reported for the prepared formulations through dialysis membrane bags. We also observed the significant reduction in biomarkers of hepatic oxidative stress, caused by OXP chemotherapy in experimental mice, thereby indicating a marked reversal of liver injury. Conclusion: We concluded that nanoemulsified astilbin can be used as therapeutic agent to counter OXP-associated oxidative stress.