High-entropy (HE) design provides ample opportunities for accessing catalysts with unique physiochemical properties for advanced energy and environmental applications. Although a variety of multi-cationic high-entropy materials (HEMs) have been identified, HEMs consisted of multiple cationic and anionic elements are still limited. Herein, we present the design and synthesis of a series of rutile-structured high-entropy oxyfluorides (HEOFs), including [RuO2]x[MgMnZnCoF2]y, [MnO2]x[MgMnZnCoF2]y, [MoO2]x[MgMnZnCoF2]y, [SnO2]x[MgMnZnCoF2]y and [TiO2]x[MgMnZnCoF2]y (x:y = 3:1, 2:1, 1:1). All the HEOFs are obtained through mechanochemical alloying rutile-structured oxide and fluoride precursors and the HEOFs inherit the crystal structures of the skeleton oxides. Moreover, the HEOFs exhibit enhanced electrocatalytic oxygen evolution reaction (OER) activity than the corresponding one-element precursors. Typically, the best-performed HEOF [RuO2]3[MgMnZnCoF2]1 catalyst requires an overpotential of 240 mV to achieve a current density of 10 mA cm−2, which is lower than RuO2 (291 mV). More impressively, the specific mass activity of [RuO2]3[MgMnZnCoF2]1 is 537.1 A gRu−1 at 1.55 V (vs RHE), which is ca. 7.6 times that of RuO2 (70.5 A gRu−1). The enhanced electrocatalytic OER performance obtained on [RuO2]3[MgMnZnCoF2]1 is ascribed to the contribution of the different cationic and anionic elements that modulates the electronic structures of the pristine RuO2, which facilitates efficient OER kinetics. This work demonstrates the efficacy of high-entropy design towards approaching excellent catalysts for enhanced electrocatalysis.