The San Francisco Estuary and its upstream watershed have been highly altered by human development following the California Gold Rush in the mid-19th century. In this paper, we explore the inter- and intra-annual variability of freshwater flow to this estuary and the resulting salt intrusion under scenarios that represent pre-development and contemporary conditions. To place this comparison in context with the advent of systematic and accurate flow and salinity measurements in the estuary, we consider an additional “pre-project” scenario that represents early 20th-century water management (circa 1920), after major flood control and reclamation but before the introduction of large water storage, diversion, and export operations. We use an observed climate record that spans 82 years to compare freshwater flow associated with the scenarios’ landscape and water use characteristics. Using published relationships between flow and salt intrusion length developed from three-dimensional hydrodynamic modeling, we evaluate the effect of these flow alterations as well as estuarine geometry modifications and historically-observed sea-level rise on salt intrusion. We conclude that the pre-development estuary exhibited a more seasonally-variable salinity regime, resulting from a more variable inflow regime from the upstream watershed.