As the only route formed in the inner Qinghai-Tibet plateau, the Tang-Tibet Ancient Road promoted the extension of the Overland Silk Roads to the inner Qinghai-Tibet plateau. Considering the Complex geographical and environmental factors of inner Qinghai-Tibet Plateau, we constructed a weighted trade route network based on geographical integration factors, and then adopted the principle of minimum cost and the shortest path on the network to simulate the ancient Tang-Tibet Ancient Road. We then compared the locations of known key points documented in the literature, and found a significant correspondence in the Qinghai section. However, there was a certain deviation between the key points recorded in Tibetan section and the simulated route; we found that the reason is the relative oxygen content (ROC) became a limited factor of the choice of the Tibetan section road. Moreover, we argue that the warm and humid climate and the human migration to the hinterland of the Qinghai-Tibet plateau were the fundamental driving forces for the formation of the Tang-Tibet Ancient Road.