The search for high-performance catalysts to improve the catalytic activity for an oxygen reduction reaction (ORR) is crucial for developing a proton exchange membrane fuel cell. Using the first-principles method, we have performed computational screening on a series of transition metal (TM) atoms embedded in monolayer Nb2S2C to enhance the ORR activity. Through the scaling relationship and volcano plot, our results reveal that the introduction of a single Ni or Rh atom through substitutional doping into monolayer Nb2S2C yields promising ORR catalysts with low overpotentials of 0.52 and 0.42 V, respectively. These doped atoms remain intact on the monolayer Nb2S2C even at elevated temperatures. Importantly, the catalytic activity of the Nb2S2C doped with a TM atom can be effectively correlated with an intrinsic descriptor, which can be computed based on the number of d orbital electrons and the electronegativity of TM and O atoms.