[en] In the present study, we introduced the nitrogenated heterocycles and fluorine atoms into the 2,5′-dibromo-4,5,2′-trihydroxyl diphenylmethanone (LM49), a bromophenol analog previously reported for its strong antioxidant ability involving in the Keap1–Nrf2 pathway. Twenty-seven fluorophenols 6a–6g, 8a–8k, 10a–10g, and 12a–12b were prepared, evaluated for their antioxidant activity in EA.hy926 cells, and investigated their interacted approach and probable mode of action with key protein Keap1 by molecular docking. Fluorophenols 6f, 8d, 8f, 8h, and 8i with EC₅₀ values ranging from 0.82 to 6.71 µM were found to be more active compared with the standard control quercetin (EC₅₀ = 18 µM). Among them, compound 8h with an EC₅₀ value of 0.82 µM showed the identical activity to lead compound LM49 (EC₅₀ = 0.7 µM). Moreover, the preferable water solubility and forming salt possibility of 8h contribute to its druggability. Further molecular docking of the optimal compound 8h with key protein Keap1 indicated that 8h stably bonded to the receptor protein by the formation of hydrogen bonds, the conjugated six-membered ring was close to the key residue Arg-415 attached to the Nrf2 on Keap1-Kelch, affecting its properties, and the change leaded to the dissociation of Nrf2 from the junction with Keap1-Kelch into the nucleus exerting its antioxidant protective effect. This study introduced a class of fluorophenols containing nitrogenated heterocycles for the development of novel Keap1-Nrf2 protein–protein interaction (PPI) inhibitors. Keap1-Kelch is suggested the most potential target protein for such class of halophenols.