Graphene and its derivatives hold great potential as support for nanocatalyst in various energy applications, such as fuel cells, batteries, and capacitors. In this work, we used density functional theory to analyze substrate effect on the electrocatalytic activity of Pt–Ni bimetallic nanoparticles for oxygen reduction reaction (ORR). The dissociative mechanism is used to evaluate the ORR performance (energy barrier for O2 dissociation, free energy of intermediates, d-band center, overpotential, and electrochemical activity) for a Pt–Ni core–shell-like nanoparticle (PtNiCS) deposited on nondefective graphene (GS) or nitrogen-doped graphene (N-GS). The electronic and catalytic properties of PtNiCS on N-GS designate N-doped graphene as the best substrate to use for ORR, showing better interaction with the bimetallic cluster, improved charge transfer between constitutes, and a superior ORR performance when compared to PtNiCS on GS. The N-GS has a significant effect in reducing the energy barrier for O2 dissociation and decrease the energetic stability of HO* intermediates, resulting in enhanced ORR activity compared with the PtNiCS on GS. In addition, the strong interaction between PtNiCS cluster and N-GS substrate may lead to an improved long-term stability of the catalytic particle during ORR cycles.