To explore the effect of halogen substitution on the sweetness inhibition properties of 2-(4-methoxyphenoxy) propionic acid (HPMP), six halogenated derivatives of HPMP were synthesized through halogen (F, Cl or Br) substitution at the 2- or 3-position of the benzene ring of HPMP and characterized structurally, and their sweetness inhibition properties were evaluated by electronic tongue. The results showed that the six halogenated derivatives could competitively inhibit sweetness. In addition, a significant dose-effect relationship was observed for the derivatives with halogen atoms introduced at the 2-position of the benzene ring. All six derivatives exhibited inhibitory effects on sucrose, fructose, glucose, xylitol and erythritol. Furthermore, the fluorinated and chlorinated derivatives showed stronger inhibitory effect on the sweetness of the aforementioned sweeteners. Therefore, it was speculated that the size and electronegativity of halogen substituents may be the key factors causing different sweetness inhibitory activity. This study indicates the importance of halogen substitution in the sweetness inhibition effect of HPMP, and provide a reliable theoretical basis for the study of the structure-activity relationship of sweetness-inhibiting compounds.