In order to further promote the application of desert sand concrete, the influence of desert sand replacing river sand with different content (25%, 50% and 75%, mass fraction) on the creep of concrete was studied by prestressed loading method, and the influence mechanism was analyzed in the combination with pore structure and microscopic morphology. The results show that the desert sand replacing 25% river sand increases the compressive strength and elastic modulus of concrete, which increase by 7.5% and 3.6% at 28 d, respectively, and reduces creep of concrete. The creep strain of concrete at 180 d is reduced by 31.7%, the specific creep at 180 d is reduced by 35.7% and the creep coefficient at 180 d is reduced by 32.1%. With the further increase of the replacement rate of desert sand, the compressive strength and elastic modulus of concrete are reduced, and the creep of concrete is improved. The desert sand replacing river sand increases the porosity with pore diameter less than 50 nm which is associated with the creep. The desert sand replacing 25% river sand reduces the porosity with pore diameter greater than 50 nm of concrete which is associated with the strength, and the internal structure of concrete is improved. With the further increase of the replacement rate of desert sand, the internal structure of concrete is loosened.