Mapping the human footprint (HF) makes it possible to quantify human influence, which has had an unprecedented impact on the global ecosystem. Using five categories of human pressure data, this study mapped the HF of the Hengduan Mountain region and assessed the effectiveness of nature reserves in reducing human impacts. The results showed that the HF of the Hengduan Mountain region was generally higher in the south and lower in the north. The HF increased by 11.24% over the past 25 years, with faster growth in the southeast. The HF growth rate in nature reserves was much lower than that across the region, which indicated that nature reserves played an important role in reducing the impact of human pressure. A study of Baimaxueshan nature reserve found that establishing nature reserves could effectively reduce the impact of human activities, and no “leakage” occurred. Population growth was an important reason for the increased HF in nature reserves. The development of ecotourism in nature reserves must be based on ecological protection. Strengthening the long-term monitoring, evaluation, and management of nature reserves is a basic requirement for their long-term development.