Droughts and resulting low flows are a threat for society, economy, and ecosystems. Droughts are natural phenomena, but anthropogenic water use can increase the pressure on water resources. To analyze the effects of changing land-use or water management and climate variability/change on water resources, models integrating the most important hydrological processes are needed. These models must account for natural processes and water resources management at different spatial and temporal scales, e.g., reservoir operation, water withdrawals. Low flow indices are analyzed for observed and simulated flows for the highly managed São Francisco river basin in Brazil, showing that during wet, normal, and moderately dry years, the existing reservoir system is able to augment low flows while during strong droughts the system reaches its limits. This effect is also represented in the simulations using the eco-hydrological model SWIM, which was adapted to account for region-specific characteristics of land-use and water management. While good to very good performance was achieved for calibration and validation for most gauges, for some gauges at tributaries only insufficient quantitative criteria are reached. The reasons for the deviation between observations and simulation results are discussed. Overall, the model is able to represent natural discharges and observed, managed discharges.