Abstract: As a key parameter of the carbon cycle within the biosphere and atmosphere, vegetation carbon use efficiency plays an important role in understanding ecosystem carbon sources and sinks. This paper analyzed the spatiotemporal patterns and trends of vegetation carbon use efficiency (CUE) in southwest China from 2001 to 2020 using Theil–Sen media trend analysis, spatial interpolation, and correlation analysis based on the MOD17A2H data. This paper focused on the response of vegetation CUE to climate changes in Southwest China using meteorological data and digital elevation model data. The results showed that (1) from 2001 to 2020, the monthly average CUE values for all vegetation types in Southwest China showed a pattern of rising, declining, rising again, and then declining again. Overall, the CUE of all vegetation types demonstrated a decreasing trend, and the decreasing rate was in the order of shrub ＞ forest ＞ grassland ＞ crop. (2) Over the past 20 years, the average annual value of vegetation CUE was about 0.75, indicating strong vegetation carbon sequestration capacity. The spatial distribution pattern revealed an increase in vegetation CUE from south and northeast China toward the northwest. Trend analysis displayed a weak downward trend in vegetation CUE across southwest China. (3) From 2001 to 2020, vegetation CUE negatively correlated with the air temperature, precipitation, and sunshine duration in Southwest China. This implies that the air temperature and sunshine duration were the dominant climatic factors affecting vegetation CUE in southwest China, whereas the impact of precipitation on vegetation CUE was relatively weak.