Demand for medium sand has increased greatly with increasing infrastructure construction items. The shortage of construction sand resources has become a serious problem in many districts. It not only increases the engineering cost, and the overexploitation of river sand and mountain as medium sand also brings a series of serious environment problems. There are abundant desert sand (DS) resources in western China. If DS resources can be used to substitute medium sand to produce desert sand concrete (DSC), which was suitable for engineering practice, the environment can be improved and engineering cost can be reduced. Although many researchers had focused on the mechanical performance of DSC, there were few documents on the frost resistance of DSC. Frost resistance experiments of DSC with 50% desert sand replacement ratio (DSRR) and ordinary concrete (OC) were performed in this paper. Influence of freeze-thaw cycles on the mechanical properties of OC and DSC was analyzed. Experimental results showed that, with increasing freeze-thaw cycles, the damage, peak strain, and porosity increased, while elastic modulus, Poisson's ratio, and peak stress declined, the stress-strain curves tended to be flat. Under the same condition of freeze-thaw cycles, the frost resistance of DSC with 50% DSRR was higher than that of OC. Constitutive model of DSC after different freeze-thaw cycles was formulated. The results predicted by constitutive model agreed well with experimental results, which can provide technical support for DSC engineering practice.