This study quantifies the effect of fertilizer and irrigation management on water use efficiency (WUE), crop growth and crop yield in sub-humid to semi-arid conditions of Limpopo Province, South Africa. An approach of coupling a cropping system model (DSSAT) with an agro-hydrological model (SWAT) was developed and applied to simulate crop yield at the field and catchment scale. Simulation results indicated that the application of fertilizer has a greater positive effect on maize yield than irrigation. WUE ranged from 0.10–0.57 kg/m3 (rainfed) to 0.84–1.39 kg/m3 (irrigated) and was positively correlated with fertilizer application rate. The combined application of the variants with deficit irrigation and fertilizer rate (120:60 kg N:P/ha) for maize turned out to be the best option, giving the highest WUE and increasing average yield by up to 5.7 t/ha compared to no fertilization and rainfed cultivation (1.3 t/ha). The simulated results at the catchment scale showed the considerable spatial variability of maize yield across agricultural fields with different soils, slopes and climate conditions. The average annual simulated maize yield across the catchment corresponding to the highest WUE ranged from 4.0 to 7.0 t/ha. The yield gaps ranged from 3.0 to 6.0 t/ha under deficit irrigation combined with 120N:60P kg/ha and ranged from 0.2 to 1.5 t/ha when only applying deficit irrigation but no fertilizer. This information can support regional decision makers to find appropriate interventions that aim at improving crop yield and WUE for catchments/regions.