The aryl hydrocarbon receptor (AhR) is a pleiotropic nuclear factor that was originally recognized as a "master" of xenobiotic metabolism but demonstrated recently to be a vital regulator of many normal physiological events. Understanding of the mechanism of action of AhR-targeted compounds, as represented by polyphenols (the greatest source of xenobiotic AhR modulators in the human diet) is of critical importance for the development of polyphenol-based nutraceutical strategies or the prevention of AHR-mediated toxicity associated with polyphenol intake. In this review, based on studies conducted over the past decade, we summarized the modes of function of polyphenolic AhR modulators. Furthermore, we made a brief mechanistic synopsis of the pharmacological/therapeutic use of polyphenols as AhR antagonists, selective AhR regulators and dual AhR/ER modulators, and underscored their potential in the prevention/treatment of common human diseases/disorders. Additionally, interesting subjects for further mechanistic investigations on polyphenolic AhR modulators have been provided.