The presence of defects and chemical dopants in metal-free carbon materials plays an important role in the electrocatalysis of the oxygen reduction reaction (ORR). The precise control and design of defects and dopants in carbon electrodes will allow the fundamental understanding of activity-structure correlations for tailoring catalytic performance of carbon-based, most particularly graphene-based, electrode materials. Herein, we adopted monolayer graphene – a model carbon-based electrode – for systematical introduction of nitrogen and oxygen dopants, together with vacancy defects, and studied their roles in catalyzing ORR. Compared to pristine graphene, nitrogen doping exhibited a limited effect on ORR activity. In contrast, nitrogen doping in graphene predoped with vacancy defects or oxygen enhanced the activities at 0.4 V vs the reversible hydrogen electrode (RHE) by 1.2 and 2.0 times, respectively. The optimal activity was achieved for nitrogen doping in graphene functionalized with oxygenated defects, 12.8 times more than nitrogen-doped and 7.7 times more than pristine graphene. More importantly, oxygenated defects are highly related to the 4e– pathway instead of nitrogen dopants. This work indicates a non-negligible contribution of oxygen and especially oxygenated vacancy defects for the catalytic activity of nitrogen-doped graphene.