The oxygen evolution reaction is the primary obstacle in the electrochemical breakdown of water; whereas transition metal selenides exhibit remarkable OER activity, their stability is compromised by the oxidative dissolution of selenium. The high-entropy materials can provide a feasible strategy to solve this problem due to their multi-element synergy and entropy stabilization effect. Here, we designed novel high-entropy MnCoCuZnAlSe2 electrocatalysts with ultra-low overpotential (190 mV@10 mA cm−2) and exceptional endurance (500 h@10 mA cm−2), which outperform other selenide and IrO2 catalysts. The high entropy effect was experimentally confirmed to inhibit selenium dissolution and improve the stability of transition metal selenides. Calculations using Density Functional Theory suggest that cobalt is actually MnCoCuZnAlSe2's true active center. The extraordinary OER properties of high-entropy selenides offer great opportunities for the design of ideal catalysts for practical applications.