Dedicated to Professor Baowen Zhang on the occasion of her 80th birthday. Despite the tremendous efforts in developing non-fullerene acceptor (NFA) for polymer solar cells (PSCs), only few researches are done on studying the NFA molecular structure dependent stability of PSCs, and long-term stable PSCs are only reported for the cells with low efficiency. Herein, the authors compare the stability of inverted PM6:NFA solar cells using ITIC, IT-4F, Y6, and N3 as the NFA, and a decay rate order of IT-4F > Y6 ≈ N3 > ITIC is measured. Quantum chemical calculations reveal that fluorine substitution weakens the C═C bond and enhances the interaction between NFA and ZnO, whereas the 𝜷-alkyl chains on the thiophene unit next to the C═C linker blocks the attacking of hydroxyl radicals onto the C═C bonds. Knowing this, the authors choose a bulky alkyl side chain containing molecule (named L8-BO) as the acceptor, which shows slower photo bleaching and performance decay rates. A combination of ZnO surface passivation with phenylethanethiol (PET) yields a high efficiency of 17% and an estimated long T 80 and Ts 80 of 5140 and 6170 h, respectively. The results indicate functionalization of the 𝜷-position of the thiophene unit is an effective way to improve device stability of the NFA.