In this study, the regional spatial-temporal variability of cadmium (Cd) in the topsoil of Guangxi, China from 2010 to 2016 was studied from data obtained from the China Geochemical Baseline Project (CGB Ⅰ and CGB Ⅱ). The driving forces of natural and anthropogenic variables were quantitatively analyzed using a geographically and temporally weighted regression model. The results showed that 1) soil Cd was highly enriched in 2010 and in soils of Hechi city in northwest Guangxi, a non-ferrous metal mining and metallurgy area, ~17% of the samples exceeded the soil contamination risk limit. In contrast, in 2016, the topsoil Cd content decreased significantly, with 7% of sites exceeding the soil risk limit. 2) Multiple factors jointly influenced the regional spatial variability of Cd. pH and organic carbon were found to be the main factors influencing Cd content and were strongly spatially correlated with Cd. Anthropogenic activities, including mining and industrial emissions, resulted in significant Cd enrichment in local areas, whereas agricultural and domestic pollutants were relatively weakly correlated with Cd. The weathering products of carbonates were significantly enriched in Cd; thus, the geological background played a significant role in the spatial variability of Cd. Soil-forming factors, including temperature, precipitation, and elevation influenced the spatial distribution of Cd, especially in the Cd background area. 3) Anthropogenic activities were the key factors influencing temporal changes in Cd. Mining caused significant enrichment of Cd in CGB Ⅰ, while industrial emissions were the primary factor for Cd enrichment in CGB Ⅱ. In addition, natural factors also played an important role; the increased Normalized Difference Vegetation Index suggested reduced desertification and reduction of soil erosion in the watershed and in pollutants transported from upstream.