Flavonoids are the major components of Apium graveolens L. root (AR). In this study, we used a rat model of high-fat emulsion die induced hyperlipidemia (HLP) to examine the antioxidant and lipid-lowering effects of the AR flavonoid extract (ARFE), and to identify its potential targets by molecular docking and western-blotting. ARFE significantly lowered the serum lipid levels in HLP rats. The lipid-lowering targets of ARFE were predicted and validated, which showed that ARFE significantly downregulated the expression levels of cholesterol synthesis-associated target proteins, including SREBP1, HMGCR and ACC1. These findings demonstrate that ARFE has remarkable lipid-lowering and antioxidant effects, and the former is mediated by the inhibition of SREBP1, HMGCR and ACC1.