AbstractFuture climate change and anthropogenic interventions can alter historical streamflow conditions and consequently degrade the health and biodiversity of freshwater ecosystems. Future ecohydrological threats, however, are difficult to quantify using the cascade of climate and hydrological models due to various uncertainties involved. This study instead uses a fully bottom‐up approach to evaluate the ecohydrological vulnerability of the Saskatchewan River Delta (SRD), the largest inland delta in North America, to changing streamflow regime and irrigation expansion. An ensemble of perturbed streamflow sequences, along with scenarios of current and expanded irrigation, was generated and fed into a regional water resource system model. Results show that the streamflow regime in the delta is more sensitive to upstream changes in annual flow volume than peak flow timing and/or irrigation expansion. The sensitivity to changes in flow volume, however, may be intensified when combined with changes in peak timing. Shifts in the upstream peak flow timing can alter the magnitude and timing of peak flow to the delta, with prime importance to aquatic biota that are adapted to historical rhythmicity in peak flows and timing. Irrigation expansion decreases the magnitude and frequency of the peak flows, alters the frequency of average and low flows, and slightly shifts the timing of the mean annual peak flow in the SRD. This can lead to isolation of lakes and wetlands from the main stream. Our results highlight the ecohydrological vulnerability of the SRD under potential changing conditions and can assist in proposing adaptation policies to protect this ecosystem.