The phenomena of global climate change and comprehensive urban expansion have precipitated significant and unprecedented transformations in landscape patterns. To enhance the assessment of these spatio−temporal changes and their driving forces at a regional level, we developed a comprehensive landscape index (CLI) to quantify these patterns and conducted a detailed analysis of the spatio−temporal variations in Minnesota over the last two decades. Our analysis of the CLI was conducted by examining both its quantitative relationships and spatial distribution patterns. The findings indicate a consistent increase in Minnesota’s CLI over this period, marked by an escalation in landscape fragmentation and diversity, alongside a decline in landscape connectivity. Temporally, the CLI experienced a notable shift in 2010. Spatially, the clustering characteristics of landscape patterns have largely remained stable. Our analysis reveals that the CLI is most sensitive to total population (POP) and gross domestic product (GDP) factors, underscoring the significant impact of human activity on landscape patterns. Notably, the explanatory capacity of interactions between factors is substantially greater than that of individual factors, with the GDP and vegetation structure (VS) interaction demonstrating the greatest influence on the spatial distribution of landscape patterns. This highlights the critical role of the interplay between human socio−economic activity and vegetation coverage in shaping landscape configurations.