Deformation along strike-slip plate margins often accumulates within structurally partitioned and rheologically heterogeneous crustal blocks within the plate boundary. In these cases, contrasts in the physical properties and state of juxtaposed crustal blocks may play an important role in accommodation of deformation. Near the San Francisco Bay Area, California, USA, the Pacific−North American plate-bounding San Andreas fault bisects the Santa Cruz Mountains (SCM), which host numerous distinct, fault-bounded lithotectonic blocks that surround the San Andreas fault zone. In the SCM, a restraining bend in the San Andreas fault (the SCM bend) caused recent uplift of the mountain range since ca. 4 Ma. To understand how rheologic heterogeneity within a complex fault zone might influence deformation, we quantified plausible bounds on deformation and uplift across two adjacent SCM lithotectonic blocks on the Pacific Plate whose stratigraphic and tectonic histories differ. This was accomplished by combining 31 new apatite (U-Th)/He ages with existing thermochronological datasets to constrain exhumation of these two blocks. Additionally, surface exposures of the latest Miocene to late Pliocene Purisima Formation interpreted in 18 structural cross sections spanning the SCM allowed construction and restoration of Pliocene deformation in a three-dimensional geologic model. We found that rock uplift and deformation concentrated within individual Pacific Plate lithotectonic blocks in the SCM. Since 4 Ma, maximum principal strain computed for the more deformed block adjacent to the fault exceeded that computed for the less deformed block by at least 375%, and cumulative uplift has been more spatially extensive and higher in magnitude. We attribute the difference in uplift and deformation between the two blocks primarily to contrasts in lithotectonic structure, which resulted from diverging geologic histories along the evolving plate boundary.