The development of efficient water-electrolysis catalysts plays a key role in clean and sustainable energy sources. In this work, 2D FeSe2 nanoplatelets have been successfully synthesized via a hydrothermal reduction route, which exhibit extraordinarily high catalytic activities and stability for oxygen evolution reaction (OER). The remarkable electrocatalytic performance of FeSe2 nanoplatelets (e.g., overpotential: 2.2 times higher than that of commercial RuO2 at 500 mV; Tafel slope: 48.1 mV/dec; steady-state current densities remain constant after 70 h) can be attributed to highly exposed active sites associated with (210) crystal faces; the 2D nanostructure could also facilitate improvement of kinetics of water oxidation. Furthermore, the changes of energy level, band structure and water adsorption ability of FeSe2 under different bias were further understood based on density functional theory calculation. Therefore, this work provides the first example of FeSe2 nanoplatelets as OER application, which may open a new avenue to design and explore other Fe-based nanostructures as efficient catalysts for renewable energy.