Ferroelectric random access memory (FeRAM) has been regarded as a promising technology for next-generation nonvolatile storage due to its excellent data storage performance and nonvolatile storage characteristics. However, fatigue degradation properties seriously impede the development and large-scale commercial use of FeRAM. In this paper, the interaction mechanism and enhancement of ferroelectric fatigue in lead zirconate titanate (PZT) thin film are investigated by the first-principles calculations (DFT). Theoretical calculations suggest that the coupling between oxygen vacancies and 180° domain walls in PZT is responsible for ferroelectric fatigue. Oxygen vacancies are more likely to be formed closer to domain wall, the “pinning” between oxygen vacancies and domain wall makes the migration of domain wall difficult, resulting in the suppression of polarization reversal and ultimately fatigue in ferroelectric thin film. The insertion of Ba(Mg_1/3Nb_2/3)O₃ (BMN) can absorb the oxygen vacancies in PZT and reduce the concentration of oxygen vacancies, and in doing so, the ferroelectric fatigue problem caused by the “pinning” effect of the oxygen vacancies can be eliminated. Moreover, the PZT thin films are deposited on Pt/Ti/SiO₂/Si(100) by the sol-gel method with using BMN buffer layer. The remnant polarization (P_r) of PZT film decreases by 51% and the PZT/BMN film remains 85% after 10¹⁰ cycles. Furthermore, it keeps stable even up to 10¹² cycles. This paper demonstrates that the PZT/BMN film with excellent ferroelectric and fatigue endurance possesses the promising applications in FeRAM.