Since the beginning of the 21st century, the economic development of Tibet has been accelerating. The Yarlung Zangbo River and its two tributaries, as the region with the largest population concentration and the fastest economic development in Tibet, has been under the dual influence of global climate warming and the intensification of human social and economic activities, where a high number of land types, such as woodland, grassland, and water areas, have been transformed into other land types, and the residential area has expanded in a disorderly manner. The ability to maintain sustainable regional development has been severely damaged. To meet the requirements of different stages of social and economic development and regional social development goals, in this study, we use the Yarlung Zangbo River and its two tributaries of Tibet as an example. Based on the Markov–PLUS model and considering the natural, social, and cultural conditions of the basin, combined with the multi-landscape simulation of land use, we predict the land use situation of the Yarlung Zangbo River and its two tributaries of Tibet in 2038. We observed the following: (i) the Markov–PLUS model has a high simulation accuracy for different land types in the study area, and can sufficiently simulate the changes in different land types in the Yarlung Zangbo River and its two tributaries of Tibet; and (ii) the simulation settings of the three landscapes basically meet the different development modes and paths of the basin in the future. There were obvious differences in the structure of land use in the basin, among which there were obvious differences, especially agricultural land and water areas. Use of the Markov–PLUS model can provide data support and references for the implementation in terms of ecological scrutiny, landscape planning, and early warnings for food production consumption security and unreasonable land use, in order to achieve the sustainable development of the basin.

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