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Net primary production (NPP) supplies matter, energy, and services to facilitate the sustainable development of human society and ecosystem. The response mechanism of NPP to land use and climate changes is essential for food security and biodiversity conservation but lacks a comprehensive understanding, especially in arid and semi-arid regions. To this end, taking the middle-reaches of the Heihe River Basin (MHRB) as an example, we uncovered the NPP responses to land use and climate changes by integrating multisource data (e.g., MOD17A3 NPP, land use, temperature, and precipitation) and multiple methods. The results showed that (a) land use intensity (LUI) increased, and climate warming and wetting promoted NPP. From 2000 to 2014, the LUI, temperature, and precipitation of MHRB increased by 1.46, 0.58 degrees C, and 15.76mm, respectively, resulting in an increase of 14.62gC/m(2) in annual average NPP. (b) The conversion of low-yield cropland to forest and grassland increased NPP. Although the widespread conversion of unused land and grassland to cropland boosted both LUI and NPP, it was not conducive to ecosystem sustainability and stability due to huge water consumption and human-appropriated NPP. Urban sprawl occupied cropland, forest, and grassland and reduced NPP. (c) Increase in temperature and precipitation generally improved NPP. The temperature decreasing <1.2 degrees C also promoted the NPP of hardy vegetation due to the simultaneous precipitation increase. However, warming-induced water stress compromised the NPP in arid sparse grassland and deserts. Cropland had greater NPP and NPP increase than natural vegetation due to the irrigation, fertilizers, and other artificial inputs it received. The decrease in both temperature and precipitation generally reduced NPP, but the NPP in the well-protection or less-disturbance areas still increased slightly.