Along the western border of the Sierra Nevada microplate, the San Andreas fault (California, United States) is comprised of three segments. Two (north and south segments) are locked and support large earthquakes (e.g., the M 7.7 1906 San Francisco and the M 7.8 1857 Fort Tejon earthquakes), while the central segment, from Parkfield to San Juan Bautista, is creeping. Based on mechanical models, we show that the late Pliocene–Quaternary convective removal (delamination) of the southern Sierra Nevada mantle lithosphere and associated uplift of the Sierra Nevada Mountains causes the Great Valley upper crust to deform by flexure and buckling. Additional three-dimensional flexural models imply that the local flexural bulge overlaps with the creeping segment of the fault system, while geological observations indicate that the local weakening of the San Andreas fault started at the same time that the Sierra Nevada started its recent phase of uplift. We argue that bending stresses promote lithostatic pore pressure to occur in the depth range of 7–15 km, causing the effective strength of the fault to vanish, and locally favoring creep. Our results suggest for the first time that earthquake cycles along a major plate boundary may be influenced by convective instabilities in the adjacent upper mantle.