Coreopsis tinctoria Nutt., an edible flowering plant, belongs to the Chrysanthemum family and is mainly grown at high altitudes in Northwestern China. It is rich in polyphenolic compounds, particularly marein and flavomarein, and possesses multiple health-promoting properties, such as antioxidant, hypoglycemic and vasorelaxant effects. Previous bioactivity investigations majorly focused on C. tinctoria and its crude extract. The aim of the present study was to prepare marein-dominant C. tinctoria flavonoids (CF), further investigate the CF protective effects of liver fibrosis induced by carbon tetrachloride and elucidate the associated molecular mechanisms. Results have demonstrated that CF effectively attenuated hepatofibrogenesis by increasing the activity of glutathione (GSH) and superoxide dismutase (SOD); suppressing the hepatic stellate cell (HSC) activation, inhibiting transforming growth factor β (TGF-β) activation and the production of α-smooth muscle actin (α-SMA), alleviating the phosphorylation of extracellular signal-regulated kinases1/2 (ERK1/2) and small mothers against decapentaplegic1/2 (Smad1/2), thus maintaining the collagen metabolic homeostasis in the liver. Our study revealed that CF possesses an efficacious protective effect against chronic hepatic fibrosis due to their strong inhibitory effects of oxidative stress and chronic inflammation.