On the basis of both geomechanical and thermal data, the San Andreas Fault (SAF) has been interpreted to act as a weak plane within much stronger crust, allowing it to slip at very low shear stresses. One explanation for this weakness is that large fluid overpressures exist locally within the fault zone. However, mechanisms for generating, maintaining, and localizing pressures within the fault are poorly quantified. Here we evaluate whether realistic sources of mantle-derived fluids, proposed on the basis of high mantle helium signatures near the SAF, can generate localized fluid pressures within the fault zone in a manner consistent with a wide range of observations along the fault and in the San Andreas Fault Observatory at Depth borehole. We first calculate a reasonable estimate of the magnitude and location of a mantle-derived flux of water into the crust. This fluid flux results from dehydration of a serpentinized mantle wedge following the northward migration of the Mendocino Triple Junction and the transition from subduction to strike-slip tectonics. We then evaluate the potential effect of this water on fluid pressures within the crust using 2-D cross-sectional models of coupled fluid flow and heat transport. We show that in models with realistic permeability anisotropy, controlled by NE dipping faults and fractures within the country rock, large localized fluid pressures can be focused within a SAF acting as a hydrologic barrier. Our results illustrate a simple and potentially plausible means of weakening the SAF in a manner generally consistent with available hydrologic, thermal, and mechanical constraints.