A strategy that employs the central‐core regiochemistry to develop two isomeric perylene diimide (PDI)‐based small molecular acceptors (SMAs), BPT‐Se and BPT‐Se1, is introduced, and the effect of the central‐core regiochemistry on the optical, electronic, charge‐transport, photovoltaic, and morphological properties of the molecules and their devices is investigated. The PDBT‐T1:BPT‐Se1‐based device delivers a power conversion efficiency (PCE) of 9.54% with an excellent fill factor (FF) of 73.2%, while the BPT‐Se‐based device yields a PCE of 7.78%. The large improvement of PCE upon isomerization of BPT‐Se should be ascribed to the concurrent enhancement of FF, short circuit current ( J_SC), and open circuit voltage (V_OC) of the PDBT‐T1:BPT‐Se1 devices. The higher FF of the organic solar cells (OSCs) based on PDBT‐T1:BPT‐Se1 can be attributed to the higher charge dissociation and charge collection efficiency, less bimolecular combination, more balanced µ_h/µ_e, better molecular packing and a more favorable morphology. It is worth mentioning that the FF of 73.2% is the highest value for PDI‐based SMAs OSCs to date. The result shows that regiochemistry of the central core in PDI‐based SMAs greatly affects the physicochemical properties and photovoltaic performance. The success of the isomerization strategy offers exciting prospects for the molecular design of PDI‐based SMAs.