The effect of fertigation regimes on wheat grown in sandy soil was tested in two field experiments in Egypt. The aim of the study was to determine the vulnerability of wheat to extreme weather event under climate change scenarios. Eight fertigation treatments, in addition to farmer irrigation were tested. Two climate change scenarios obtained from Hadley climate change model were incorporated in CropSyst model to assess wheat yield responses to fertigation regimes under these scenarios. The results showed that the highest yield and the highest water use efficiency (WUE) was obtained under irrigation application using 1.2 and 0.8 of Etc, respectively, with fertigation application in 80% of application time in both growing seasons. The calibration of CropSyst model confirmed that the model is able to mimic the growth of wheat and predicted grain, biological yield, and WUE with high degree of accuracy. The highest yield reduction and the lowest WUE under the tested climate change scenarios were obtained from farmer irrigation. It can be concluded that irrigating wheat grown in sandy soil with an amount of either 1.0 or 0.8 of ETc with fertigation application in 80% of application time is recommended to enhance growth and yield, and to reduce wheat's damage caused by extreme climate change.