The Wujiang River Watershed in Guizhou province is one of the most important plateau mountain basin in Southwest China. It is of great significance to examine the relationship between population distribution and topography of this watershed. This paper can help to understand the impact of the geographical environment of the study area on population distribution. The article selects digital elevation model (DEM) data and population raster data, and uses digital elevation model (DEM) to extract topographic factors such as altitude, slope, and topographic relief. Then, it studies the relationship between topographic factors and population distribution. Some conclusions can be drawn as follows. (1) The population of the study area is inportantly distributed between 800 and 1400 m, accounting for more than 60%, and the highest population density is found between 1000 and 1200 m. (2) As the slope increases, the population and population density are in a downward trend. When the slope is less than 5 ^o, the population density is more than 500 people/km ². It is also shown, to a certain extent, that the slope has a restrictive effect on human activities and is one of the key topographic factors that affect the population distribution. (3) With the rise of topographic relief, the population density generally shows a downward trend. When the topographic relief is less than 50 m, the population density exceeds 1000 people/km ². Topographic relief is an important factor affecting population distribution. The results could provide a reference for the local government to formulate policies on population and eco-environment protection so as to achieve harmony between nature and people. In addition, this article can be further expanded in the following aspects: (1) using the latest population raster data to analyze the relationship between population and topography, and explore the characteristics and laws of population changes in the watershed in the background of rapid economic development in Guizhou province in recent years; (2) using the digital elevation model (DEM) with a lower accuracy to analyze the relationship between population and topography.