The extent to which landscape spatial patterns can impact the dynamics and distribution of biodiversity is a key geography and ecology issue. However, few previous studies have quantitatively analyzed the spatial relationship between the landscape pattern and habitat quality from a simulation perspective. In this study, the landscape pattern in 2031 was simulated using a patch-generating simulation (PLUS) model for the Yellow River Basin. Then, the landscape pattern index and habitat quality from 2005 to 2031 were evaluated using the Fragstats 4.2 and the Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST) model. Furthermore, we analyzed the spatial distribution characteristics and spatial spillover effects of habitat quality using spatial autocorrelation analysis. Finally, the spatial association between the landscape pattern index and habitat quality was quantitatively revealed based on a spatial lag model. The simulation results showed that: (1) from 2005 to 2031, the landscape of the Yellow River Basin would be dominated by grassland and unused land, and the areas of construction land and water body will increase significantly, while the area of grassland will decrease; (2) patch density (PD) and Shannon’s diversity index (SHDI) show significant increases, while edge density (ED), landscape shape index (LSI), mean patch area (AREA_MN), and contagion index (CONTAG) decrease; (3) from 2005 to 2031, habitat quality would decrease. The high-value areas of habitat quality are mainly distributed in the upper reaches of the Yellow River Basin, and the low-value areas are distributed in the lower reaches. Meanwhile, both habitat quality and its change rate present positive spatial autocorrelation; and (4) the spatial relationships of habitat quality with PD and COHESION are negative, while ED and LSI have positive impacts on habitat quality. Specifically, landscape fragmentation caused by high PD has a dominant negative influence on habitat quality. Therefore, this study can help decision makers manage future landscape patterns and develop ecological conservation policy in the Yellow River Basin.