Molecular nano-architecture enables selective chemical interactions and efficient separation based on size and charge species. However, effectively separating size-similar, uncharged aqueous contaminants remains a significant challenge. Herein, we propose a precise intermolecular force regulation strategy for efficient separation of similarly sized, uncharged, water-soluble small molecules using nanoporous polyamide membranes with tunable pore chemistry. Molecular dynamics and density functional theory simulations demonstrate that regulation by pore-wall molecular forces—assisted by pore size—can effectively differentiate water–pore wall–solute interaction forces, simultaneously achieving triple effects: decisively reduced water–pore wall friction, capably enhanced solute–pore wall friction, and competently discriminated water–solute interactions. Ultimately, pore wall molecular force regulation unlocks remarkable selective transport performance in water–solute separation, delivering an extraordinary 90-fold increase in selectivity alongside nearly a 10-fold enhancement in water permeance, all without sacrificing efficiency. These investigations offer substantial potential for energy-efficient water treatment and small molecular sieving applications, where achieving high permselectivity is crucial for optimal operational efficiency.