Lonicerae japonicae Flos (LJF) is a natural plant containing abundant antioxidant ingredients. In order to extract more antioxidants from LJF, in this study, a novel strategy was proposed for optimizing the extraction factor level by response surface methodology with a tailored deep eutectic solvent (DES) as the extraction solvent and antioxidant ability as the evaluation index. After optimizing the composition of DES and the extraction condition, the extracts obtained by our proposed method yielded better antioxidant ability (229.1–249.1 μmol TE/g DW) and higher antioxidant contents (34.2–36.5 mg GAE/g DW for total phenolics and 119.6–123.0 mg RE/g DW for total flavonoids) from LJF in 5 min without organic solvent consumption that were significantly superior to the Chinese Pharmacopoeia extraction method. The K-T solvation parameter and a scanning electron microscope were adopted to explore the extraction mechanism, and the results showed that the polarity and damage effect on plant cells of DES were crucial for the extraction of antioxidants. In addition, after combining the HPLC fingerprint and partial least squares model, chlorogenic acid, rutin, and 3,5-O-Dicaffeoylquinic acid were screened as the antioxidant Q-markers of LJF. This work demonstrates that an optimization strategy based on antioxidant ability and tailored DES has the potential to extract more antioxidants from natural plants.