It has been proposed that isotope effects could effectively downshift intramolecular vibrational frequencies of light harvesting materials, thereby reducing the non-radiative recombination from the charge-transfer (CT) state to the ground state (GS) and achieving a smaller non-radiative energy loss (delta Eloss non-rad) theoretically in organic solar cells (OSCs). However, there are no systematic experimental studies to address such a crucial issue: can isotope effects enable OSCs to achieve a smaller delta E-loss(non-rad) and why? Herein, we constructed 29 non-fullerene acceptors (NFAs) by isotope substitution on different functional groups based on four high-performance NFA systems and further investigated their photovoltaic performance systematically. Large-scale statistical experimental and theoretical analyses indicate no significant difference of PCE and delta E-loss(non-rad) due to the intrinsically very weak electron-vibration coupling between the CT state and GS (EVCCT-GS) and largely unimpacted coupling strength (tCT-LE) between the CT and local exciton states. Also based on theoretical results from the Huang-Rhys factor, although different vibration modes could have different influences on the strength of EVCCT-GS, all are quite small. Both experimental and theoretical results suggest that an isotope strategy may not be a feasible way to significantly improve PCEs of high-performance OSCs by reducing delta E(loss)(non-rad )at the current stage.