The Manasi region is located in an arid and semi-arid region with fragile ecology and scarce resources. The land use change prediction is important for the management and optimization of land resources. We utilized Sankey diagram, dynamic degree of land use, and landscape indices to explore the temporal and spatial variation of land use and integrated the LSTM and MLP algorithms to predict land use prediction. The MLP-LSTM prediction model retains the spatiotemporal information of land use data to the greatest extent and extracts the spatiotemporal variation characteristics of each grid through a training set. Results showed that (1) from 1990 to 2020, cropland, tree cover, water bodies, and urban areas in the Manasi region increased by 855.3465 km2, 271.7136 km2, 40.0104 km2, and 109.2483 km2, respectively, whereas grassland and bare land decreased by 677.7243 km2 and 598.5945 km2, respectively; (2) Kappa coefficients reflect the accuracy of the mode’s predictions in terms of quantity. The Kappa coefficients of the land use data predicted by the MLP-LSTM, MLP-ANN, LR, and CA-Markov models were calculated to be 95.58%, 93.36%, 89.48%, and 85.35%, respectively. It can be found that the MLP-LSTM and MLP-ANN models obtain higher accuracy in most levels, while the CA–Markov model has the lowest accuracy. (3) The landscape indices can reflect the spatial configuration characteristics of landscape (land use types), and evaluating the prediction results of land use models using landscape indices can reflect the prediction accuracy of the models in terms of spatial features. The results indicate that the model predicted by MLP-LSTM model conforms to the development trend of land use from 1990 to 2020 in terms of spatial features. This gives a basis for the study of the Manasi region to formulate relevant land use development and rationally allocate land resources.