Dislocations are emerging as a pivotal factor for tailoring the functional and mechanical properties of ceramics. The introduction of point defects, notably oxygen vacancies, is unavoidable during the conventional sintering process in polycrystalline ceramics. Understanding the interplay between dislocations and oxygen vacancies is necessary for its profound implications. In this work, an innovative approach is implemented to regulate the dislocation-based incipient plasticity and creep behavior in (K0.5Na0.5)NbO3 (KNN)-based ceramics through oxygen vacancy engineering via CuO “hard” doping. Nanoindentation pop-in tests reveal that increasing oxygen vacancy concentrations significantly promotes the nucleation and activation of dislocations. Theoretical calculations based on Density Functional Theory further corroborate that oxygen vacancies contribute to a decrease in Peierls stress and total misfit energy, facilitating dislocation nucleation and activation. Nanoindentation hardness and creep behavior demonstrate oxygen vacancy impedes dislocation mobility due to solute strengthening and pinning effect. The effect of oxygen vacancies is elucidated through diverse mechanisms related to the interaction between dislocations and oxygen vacancies at different stages. This oxygen vacancy-induced strengthening and toughening strategy displays a significant potential to improve the mechanical properties of piezoelectric ceramics while still maintaining high electrical performance.