To investigate the applicability of the DSSAT model to the drip irrigation under mulch of cotton in southern Xinjiang and find out optimal irrigation schedule, the DSSAT-CROPGRO-Cotton model parameters were calibrated and validated by field measurement data of flowering date, maturity date, yield, and aboveground biomass in 2018 and 2019. The highyielding and watersaving irrigation scheme was obtained by continuously adjusting the irrigation quotas. The results showed that the relative rootmeansquare error (nRMSE) of the CROPGRO-Cotton model was less than 10% for simulating flowering date, maturity date, and cotton yield of cultivar “Xinluzhong 46”, while the nRMSE was less than 20% for the simulation of aboveground biomass. The consistency index (d) of flowering date, maturity date, yield, and aboveground biomass of cotton was greater than 0.85, indicating a good simulation effect of the model. Using meteorological data from 2017 to 2020, the optimal irrigation scheme was obtained, with irrigation volume, yield and wateruse efficiency being accounted for. When the daily difference between the cumulative crop evapotranspiration and precipitation (ETC-P) of cotton field reaches 25 mm, an irrigation quota of 27 mm is implemented, with 297 mm of irrigation quota in total during whole growing period, which is an optimal irrigation schedule considering both yield and water use efficiency.