Sustainable agriculture in intensively irrigated watersheds, particularly those in arid and semi-arid regions, requires enhanced management practices to maintain crop production, which depends on climate, available water resources, soil conditions, irrigation practices, and crop type. Among these factors, soil salinity and climate change are significant challenges to agricultural productivity. To investigate the long-term influence of salinity and climate change on crop production from 1999 to 2100 in irrigated semi-arid regions, we apply the water footprint (WF) concept using the hydro-chemical watershed model SWAT-MODFLOW-Salt, driven by five General Circulation Models (GCMs) and two climate scenarios (RCP4.5 and RCP8.5), to a 732 km2 irrigated stream-aquifer system within the Lower Arkansas River Valley (LARV), Colorado, USA. The study focused on calculating the green (WFgreen), blue (WFblue), and total (WFtotal) crop production WFs for 29 crops in the region, with and without including salinity effect on crop yield. Results reveal that during the baseline period (1999–2009), the total annual average WFgreen, WFblue, and WFtotal increased by 7.6 %, 4.4 %, and 6.5 %, respectively, under salinity stress, as crops experienced reductions of up to 4.6 %, 1.6 %, and 2.3 % in green, blue, and total crop yield. The mutual impact of salinity and the worst-case climate model (IPSL_CM5A_MR) under the higher emission scenario (RCP8.5) led to a 3.3 %, 1.9 %, and 3 % increase in green, blue, and total crop production WFs. Furthermore, the study highlighted that the proportion of green, blue, and total crop production WFs in the LARV exceeded the world average. This discrepancy was attributed to various factors, including different spatial and temporal crop distribution, irrigation practices, soil types, and climate conditions. Notably, salinity stress affected green crop yield and green WF more significantly than blue crop yield and blue WF across all GCM models. This finding underscores the importance of prioritizing management practices to control salinity-associated challenges within the region.