Development of low-cost and high-efficiency electrocatalysts for overall water splitting is of great significance in the sustainable hydrogen economy. Herein, Fe 1.2 (CoNi) 1.8 Se x medium-entropy metal selenides (MESes) nanoparticles are prepared via the selenylation of metal-organic frameworks (MOFs) precursors. The optimal Fe 1.2 (CoNi) 1.8 Se 6 MESe exhibits an outstanding electrocatalytic performance in alkaline media, offering low overpotentials of 66 and 216 mV at 10 mA cm −2 for the hydrogen evolution reaction and oxygen evolution reaction, respectively. A full electrolysis apparatus with Fe 1.2 (CoNi) 1.8 Se 6 MESe as both cathode and anode displays an excellent performance, achieving 10 mA cm −2 at a potential of 1.55 V. Furthermore, density functional theory calculations demonstrate that the formation of MESe enhances the surface charge density and brings the d-band center closer to Fermi level, as compared with that of the MOF precursor. Overall, the proposed strategy of medium-entropy materials presents a low-cost approach to fabricate energy storage and conversion devices.