Revealing the potential and nanoparticle size effect is significant for understanding the electrochemical microkinetic behaviors under real reaction conditions. Herein, an efficient strategy of combining the robust fully converged constant potential (FCP) algorithm and the size dependent site distribution rule assumption was proposed. A simple reaction of isotopic D2O/H2O adsorption and dissociation on Pt nanoparticles was set as the model reaction. The results show that the cathodic negative potential and the anodic positive potential would result in the D2O orientation of the D-down/O-down physisorption configuration. Microkinetic simulations by this strategy obtained electrochemical widows for D2O/H2O dissociation, and the optimal Pt nanoparticle diameter was predicted to be 1.8 nm, which agrees well with the experimental observation of ∼2 nm threshold. The kinetic isotope effect (KIE) rate constant ratio at the optimal potential of -0.80 V vs SHE was calculated to be ∼1.83. This work provides a guideline in studying electrochemical electrode-electrolyte interactions on nanoparticles.