In most watershed-modeling studies, flow is calibrated at one monitoring site, usually at the watershed outlet. Like many arid and semi-arid watersheds, the main reach of the Santa Cruz watershed, located on the Arizona-Mexico border, is discontinuous for most of the year except during large flood events, and therefore the flow characteristics at the outlet do not represent the entire watershed. Calibration is required at multiple locations along the Santa Cruz River to improve model reliability. The objective of this study was to best portray surface water flow in this semi-arid watershed and evaluate the effect of multi-gauge calibration on flow predictions. In this study, the Soil and Water Assessment Tool (SWAT) was calibrated at seven monitoring stations, which improved model performance and increased the reliability of flow predictions, in the Santa Cruz watershed. The most sensitive parameters to affect flow were found to be curve number (CN2), soil evaporation and compensation coefficient (ESCO), threshold water depth in shallow aquifer for return flow to occur (GWQMN), base flow alpha factor (Alpha_Bf), and effective hydraulic conductivity of the soil layer (Ch_K2). In comparison, when the model was established with a single calibration at the watershed outlet, flow predictions at other monitoring gauges were inaccurate. This study emphasizes the importance of multi-gauge calibration to develop a reliable watershed model in arid and semi-arid environments. The developed model, with further calibration of water quality parameters will be an integral part of the Santa Cruz Watershed Ecosystem Portfolio Model (SCWEPM), an online decision support tool, to assess the impacts of climate change and urban growth in the Santa Cruz watershed.