The Ganges River delta complex contains a transboundary aquifer system shared between India and Bangladesh. Although it serves as the main freshwater source for the population inhabiting the delta, the aquifer system is severely contaminated with arsenic (As). This study aimed to determine the control of the delta hydrostratigraphy on the regional-scale depth distribution of As within the aquifer system. We developed the first high-resolution, regional-scale, transboundary hydrostratigraphic model of the Ganges River delta and analyzed the patterns of As distribution as a function of the hydrostratigraphy. Model results indicate that, despite the presence of a single aquifer system across the delta, the hydrostratigraphy is spatially variable and can be architecturally divided into three distinct aquifer subsystems from northwest to southeast: a single, thick continuous aquifer (type I); a vertically segregated, semi-confined aquifer subsystem (type II); and a multilayered, nearly confined aquifer subsystem (type III). Results indicate that the spatial distribution of As is characteristically different in each subsystem. In the type I aquifer, As concentrations tend to be homogeneous at all depths, while in type II and type III aquifers, As concentrations sharply decrease with depth. The intervening aquitards in the type II and type III aquifer subsystems appear to act as natural barriers to infiltration of surficial As or organic matter–rich water to the deeper aquifer zones. This delineation of the regional-scale hydrostratigraphic architecture and resulting understanding of its plausible controls on the depth-distribution of As within the delta should significantly aid in the systematic framing of sustainable management plans for the As-safe aquifers within the Ganges River delta aquifer system.