Cotton is an important crop in Arizona, with a total cash value of approximately $200 million for fiber and cottonseed in 2018. In recent years, heat stress from increasing air temperature has reduced cotton productivity in the Arizona low desert (ALD); however, the effects of future climate on ALD cotton production have not been studied. In this study, the DSSAT CSM-CROPGRO-Cotton model was used to simulate the effects of future climate on cotton growth, yield, and water use in the ALD area. Projected climate forcings for the ALD were obtained from nine global climate models under two representative concentration pathways (RCP 4.5 and 8.5). Cotton growth, yield, and water use were simulated for mid-century (2036 to 2065) and late century (2066 to 2095) and compared to the baseline (1980 to 2005). Results indicated that seed cotton yield was reduced by at least 40% and 51% by mid-century and late century, respectively, compared to the baseline. Of all the weather variables, the seasonal average maximum (R-2 = 0.72) and minimum (R-2 = 0.80) air temperatures were most correlated with yield reductions. Under the future climate conditions of the ALD, cotton growth or biomass accumulation slightly increased compared to the baseline. Irrigation requirements in the ALD increased by at least 10% and 14% by mid-century and late century, respectively. Increases in irrigation requirements were due to an increase in crop water use; hence, greater demand for freshwater withdrawal for agricultural purposes is anticipated in the future. Therefore, cotton cultivars that are tolerant of long periods of high air temperature and improved management practices that promote efficient crop water use are critical for future sustainability of cotton production in the ALD.