Recent large-scale seismological observations have shown that off-fault strain localization and foreshock migration could serve as an early warning of an impending earthquake. However, this process is still largely unknown. In this study, state-of-the-art friction experiments were conducted in a oil-confined biaxial shear apparatus to investigate the link between stick-slip nucleation and off-fault deformation. Our findings indicate that there is a direct link between stick-slip nucleation and off-fault deformation, provided that the fault is conditionally unstable (a − b < 0). Inelastic off-fault deformation may trigger unstable slip by decreasing the stiffness of the surrounding rock volume, which favors earthquake nucleation. Additionally, the study presents laboratory observation of precursory strain localization around a fault during stick-slip cycles. These findings suggest that volumetric deformation processes could be a main factor in the nucleation of large ruptures and strain localization could be a reliable harbinger of large earthquakes.