Perilla frutescens are popular plant in East Asia, and the leaves of perilla were known for antioxidant, anti‐allergic, anti‐inflammatory and anti‐tumor effect. According to our previous study, P. frutescens included two major polyphenolic compounds, caffeic acid and rosmarinic acid. Previous our study showed protective effect of P. frutescens extract (PLE) on oxidative hepatotoxicity. Our group isolated of caffeic acid from P. frutescens and it enhanced γ‐glutamylcysteine synthetase activity and glutathione level. Based on high performance liquid chromatography analysis data, PLE have 1.32 μg caffeic acid/mg dry material (DM) and 26.84 μg rosmarinic acid/mg DM. And in vitro study showed that PLE and its constituents have protective effect on t‐ BHP‐induced oxidative stress in HepG2 cells. Also, in vivo study showed pretreatment with PLE (1000 mg/kg b.w.), caffeic acid (1.32 mg/kg b.w.) and rosmarinic acid (26.84 mg/kg b.w.) for 5 days before a single dose of t‐ BHP (i.p. 0.5 mmol/kg b.w.) lowered lipid peroxidation level and increased the reduced form of glutathione. And mixed caffeic acid and rosmarinic acid has more protective effect than single dose of compound on oxidative stress. Therefore, we conclude that caffeic acid and rosmarinic acid from Perilla frutescens has synergistic protective effect on oxidative stress in vitro and in vivo . Grant Funding Source : Ministry of Education, Science and Technology. Korea