Topographic relief is a key factor limiting population distribution and economic development in mountainous areas, especially in the transition zone from mountains to plains. Taking the southern Anhui mountainous area as an example, based on the digital elevation model (DEM) with a resolution of 30 m, we used ‘quadratic’ mean change-point analysis to calculate the optimal statistical unit, and then extracted the topographic relief. Taking the county as the unit of analysis, two indicators of population density and economic density were selected. Spatial statistics and correlation analysis were used to quantitatively analyze the impact of topographic relief on population and economy. Finally, the impact of slope and elevation was analyzed. The following results were obtained. (1) The topography of the study area was dominated by medium relief (200–500 m), followed by small relief (70–200 m), flat (0–30 m), and slight relief (30–70 m), and a small proportion of large relief (≥500 m). (2) The impact of topographic relief on population and economy was slightly stronger than that of slope and elevation. The impact on population distribution was stronger than that on economic development. The impact on primary industry was stronger than that on secondary and tertiary industries. (3) In the southern Anhui mountainous area, 72.35% of the population and 76.72% of GDP were distributed in the area with a topographic relief of 155 m or less, while the land area only accounted for 43.93%. The area with a topographic relief greater than 245 m accounted for 28.76%, but only 10.69% of the population, and only 8.34% of GDP. The population distribution and economic development were obviously concentrated in the low topographic relief area. However, the characteristics of high topographic relief not only hindered the agricultural mechanization and limited the development of the primary industry, but also had a significant impact on infrastructure development, investment, and industrial layout, thus weakening regional economic advantages. In the future, the economic level of these areas needs to be improved.