Natural flow regimes in deep unsaturated zones of arid interfluvial environments are rarely in hydraulic equilibrium with near-surface boundary conditions imposed by present-day plant–soil–atmosphere dynamics. Nevertheless, assessments of water resources and contaminant transport require realistic estimates of gas, water, and solute fluxes under past, present, and projected conditions. Multimillennial transients that are captured in current hydraulic, chemical, and isotopic profiles can be interpreted to constrain alternative scenarios of paleohydrologic evolution following climatic and vegetational shifts from pluvial to arid conditions. However, interpreting profile data with numerical models presents formidable challenges in that boundary conditions must be prescribed throughout the entire Holocene, when we have at most a few decades of actual records. Models of profile development at the Amargosa Desert Research Site include substantial uncertainties from imperfectly known initial and boundary conditions when simulating flow and solute transport over millennial timescales. We show how multiple types of profile data, including matric potentials and porewater concentrations of Cl−, δD, δ18O, can be used in multiphase heat, flow, and transport models to expose and reduce uncertainty in paleohydrologic reconstructions. Results indicate that a dramatic shift in the near-surface water balance occurred approximately 16000 yr ago, but that transitions in precipitation, temperature, and vegetation were not necessarily synchronous. The timing of the hydraulic transition imparts the largest uncertainty to model-predicted contemporary fluxes. In contrast, the uncertainties associated with initial (late Pleistocene) conditions and boundary conditions during the Holocene impart only small uncertainties to model-predicted contemporaneous fluxes.