Farmland is a key resource for safeguarding the regional food security and social stability, particularly in Tibet where the farmland is very limited due to its high altitude. With quick economic development during recent decades, farmland changes are great in China, and thus have been extensively studied. These studies generally focused on eastern regions, and seldom for Tibet due to the lack of good quality and available data. To this end, taking the Three River Region (TRR) as the case area, this study obtained 1 m spatial resolution farmland data for 2000 and 2018 by visual interpretation of the Google Earth high resolution satellite images, and then analyzed the farmland change, its driving factors and impact on grain production between 2000 and 2018. The results showed that farmland in the TRR decreased by 8.85% from 219.29 k ha in 2000 to 199.89 k ha in 2018, averagely reduced by 0.51% per year, mainly driven by the economic development, agricultural progress, urbanization, and population growth. The farmland losses largely occurred in urban areas and their surrounding counties due to urban land occupation, and caused the grain production reduced by 9.38%. To control the quick farmland losses and to ensure the regional food security of Tibet, it should strengthen the supervision on non-agricultural occupation of farmland and increase agricultural investment to improve the land productivity in the TRR.