Two-dimensional (2D) nanomaterials with grain boundary defects are attractive to researchers in many fields, such as energy conversion and storage, sensing, catalysis and biological medicine. In this work, a nanostructure of 2D Fe-doped NiO nanosheets (NiFe_xO) with grain boundary defects was designed and applied in the electrocatalytic oxygen evolution reaction. This nanomaterial was synthesized through a solvothermal strategy followed by a thermally driven conversion process. In general, NiFe_xO electrocatalysts were fabricated with gradual morphological variation depending on the atomic ratio of Ni : Fe. It is surprising that the Fe content determines the electrocatalytic performance and the overpotential of water oxidation exhibits an inverted volcanic pattern. As expected, the as-prepared 2D NiFe_0.1O nanosheets with grain boundary defects exhibit enhanced OER activity (274 mV@10 mA cm⁻²) compared with the oxide electrocatalyst reported in 1.0 M KOH owing to the advantages of abundant active sites. This work will shed light on the design and fabrication of novel-structured nanocatalysts.