ObjectiveThis study aimed to determine the optimal extraction process and examine whether the combination of Flos Sophorae Immaturus (FSI) and Yupingfeng san (YPS) has a synergistic effect on free radical scavenging capacity. Design and methodsThe time of immersion and extraction and the ratios (material/solvent) of the combination of YPS and FSI were optimized on the basis of polysaccharide and flavonoid yields via orthogonal design. The optimal result was used in the 1,1-diphenyl-1-picrylhydrazyl (DPPH) assay and animal experiments to test the antioxidant activity, which is reflected by superoxide dismutase, malondialdehyde, glutathione peroxidase, and total antioxidant capacity serum levels. The optimal extraction process was determined using various ingredients to obtain complex extracts with high active ingredient content and antioxidant activity. DPPH assay results showed that the optimized ingredients have antioxidant effects, and the combination had better antioxidation function than YPS in vitro. The combination also showed synergistic antioxidant activity compared with YPS in vivo. ConclusionsThe combination of YPS and FSI had a synergistic antioxidant effect in vitro. The optimized extracts had antioxidant effects in vivo. These results indicated that YPS could be used with FSI to improve its antioxidant capacity in the body on the basis of free radical scavenging capacity.