Metal oxyhydroxides produced by the surface reconstruction were widely considered as active catalytic species in the oxygen evolution reaction (OER). However, simultaneous activation of metal sites in surface oxyhydroxides remains a great challenge. In this study, the interface self-activation strategy was utilized to simultaneously activate both the iron and nickel sites at the surface oxyhydroxides of (Fe,Ni)OOH-NiSe2 nano heterostructure. The OER activity was greatly boosted by the dual activation of active sites, resulting in an overpotential of 245 mV@100 mA cm−2 with a small Tafel slope of 44 mV dec−1. The finely constructed FeOOH-NiSe2 heterostructure was transformed into (Fe,Ni)OOH-NiSe2 through the formation of distinct bonds of M(Fe,Ni)-O-Se during the OER process, which was discovered through a combination of experimental studies with DFT calculations. A fast OER reaction dynamic was achieved due to the unique self-optimized interface structure which produced a dual synergistic effect between the interface structure and the active sites of Fe and Ni of oxyhydroxides, modulated the electronic structure and d band center of active sites, and increased the number of optimum active sites. This work paves a way to design high-performance electrocatalysts with multiple active sites for other electrochemical reactions.