Integrated management of surface water and groundwater is the key to achieve sustainable water resources and secure water availability, especially in arid and semi-arid regions of the world. With generally scarce surface water resources, groundwater often is the primary source of water supply in such regions, with significant groundwater-surface water (GW/SW) interactions often occurring in irrigated regions. The objective of this study is to quantify the variation in stream seepage and groundwater discharge fluxes in an agro-urban river basin as impacted by climate change. To achieve this goal, i) an integrated hydrologic modeling code that accounts for groundwater and surface water processes and exchanges in large regional-scale managed river basins is developed for the South Platte River Basin (72,000 km²), Colorado, and ii) possible future impacts imposed by climate change on surface water and groundwater exchange in a basin-scale complex semi-arid region is assessed. The developed updated version of SWAT-MODFLOW is forced with five different CMIP5 climate models downscaled by Multivariate Adaptive Constructed Analogs (MACA), each for two climate scenarios, RCP4.5, and RCP8.5, for 1980-2100. The projected GW/SW fluxes from 2000 through the end of the century are presented in 4 different time intervals along the South Platte River and its tributaries- current (2000-2020), near future (2021-2040), mid-century (2041-2070), and end of the century (2071-2100) in dry (February) and wet (May) months of the year. The changes in stream seepage and groundwater discharge fluxes in dry and wet months of the year follow different patterns, as groundwater discharge to streams decreases during the dry months while the water table elevation declines. Overall, under the most extreme climate condition groundwater discharge will decrease by approximately 10% by 2100.