Rapid urban expansion has significantly altered the regional landscape pattern, posing a serious threat to the sustainable development of natural and social ecosystems. By using landscape patterns indices and an area transfer matrix, this study analyzed the spatial-temporal changes of landscape patterns in the karst mountainous cities of southwest China from 2000 to 2020, by taking the central urban area of Guiyang City (CUAG) as the study area. This study explored the spatial and temporal driving factors of landscape pattern changes by using stepwise multiple linear regression and geographic detector methods. The results show: (1) CUAG’s landscape types altered changed drastically, with the area of forestland and construction land rapid increment and cultivated land decrement significantly. (2) The patches of construction land and forestland tended to be aggregated, the degree of fragmentation was reduced, and the shape was complex; cultivated land fragmentation was intensified. The connectivity of the landscape was improved, while the level of landscape diversity declined, the trend of landscape homogenization was obvious. (3) Socioeconomic and geographical endowment drivers have determined landscape pattern changes. The findings of this study may be used to interpret other similar landscapes worldwide and may imply the protection of urban ecosystem and sustainable development.