Side-chain engineering has been considered as one of the most promising strategies to optimize non-fullerene small-molecule acceptors (NFSMAs). Previous efforts were focused on the optimization of alkyl-chain length, shape, and branching sites. In this work, we propose that asymmetric side-chain engineering can effectively tune the properties of NFSMAs and improve the power conversion efficiency (PCE) for binary non-fullerene polymer solar cells (NFPSCs). Specifically, by introducing asymmetric side chains into the central core, both of the absorption spectra and molecule orientation of NFSMAs are efficiently tuned. When blended with polymer donor PM6, NFPSCs with EH-HD-4F (2-ethylhexyl and 2-hexyldecyl side chains) demonstrate a champion PCE of 18.38% with a short-circuit current density (J SC ) of 27.48 mA cm −2 , an open circuit voltage (V OC ) of 0.84 V, and a fill factor (FF) of 0.79. Further studies manifest that the proper asymmetric side chains in NFSMAs could induce more favorable face-on molecule orientation, enhance carrier mobilities, balance charge transport, and reduce recombination losses.