Developing highly active electrocatalysts with rich oxygen vacancies and precisely distributed metal sites holds exceptional promise for various renewable and sustainable energy technologies. However, the great challenge is to ensure the stability of oxygen vacancies (VO) during the oxygen evolution reaction (OER) process. Herein, we implement an innovative approach to produce a highly active and stable OER electrocatalyst by plasma-enabled Fe doping of Co-based 2D metal–organic framework (MOF) nanosheets, followed by a carbonization process to fabricate unique triangular-shaped “cheese-like” Fe/Co–carbon nanosheets with a mesoporous structure, and densely and evenly distributed reactive centers, and without damaging the frameworks. The O2–Ar radio frequency (RF) plasma ensured two critical effects, namely oxygen vacancy generation, and forming and modifying the oxidation states of the catalytically active metals in the framework leading to high OER performance. It is shown that filling the oxygen vacancies with Fe heteroatoms helps tune the atomic sites of the two metals in the MOFs and achieve a unique heterostructure where electron currents can be directed between metal sites of different oxidation states. Benefiting from the demonstrated unique advantages of our plasma-enabled approach, the optimized Fe1Co3/VO-800 exhibits a significantly enhanced OER performance and long-term stability, evidenced by a low overpotential of 260 mV at 10 mA cm−2 and a small Tafel slope of 53 mV dec−1. This work provides a new effective approach for the development of next-generation electrocatalysts for diverse applications in environmental and energy fields.