<p>Understanding the impacts of human activities on the plateau’s living environment is essential for advancing modernization pathways that promote harmony between humanity and nature. However, studies on the dynamic interactions between human activities and the living environment on the Qinghai-Xizang Plateau (QXP) remain limited, with a paucity of quantitative relationship analyses. This study established an assessment framework to evaluate human influences on the living environment in QXP, using data on typical human activities, ecological conditions, and human settlements. Within this framework, the spatial analysis methods and the coupling coordination model were used to examine the spatio-temporal characteristics and relationship of human activities and living environment on the QXP from 2000 to 2020. The geographical detector model was then applied to identify the key factors influencing the plateau’s human living environment. Subsequently, the four-quadrant analysis model was adopted to assess human influences on the living environment. The results indicate that the human activity intensity (HAI) on the QXP remained relatively low yet increased by 15.41% from 2000 to 2020. Spatially, the human living environment quality (LEQ) improved from northwest to southeast, with 61.14% of the areas remaining stable and 18.47% experiencing slight improvement. The analysis of coupling coordination revealed a continuous improvement between the HAI and LEQ, with the areas of high and relatively high coordinated types increasing by more than 9%. Precipitation and urban-rural construction were identified as the primary factors influencing changes in the LEQ. The interaction between the HAI and LEQ was strengthening, with 40.44% classified as coordinated development type and 38.35% as development-environment conflict type. These findings provide valuable insights for enhancing the resilience of human settlements and promoting green development across the plateau.</p>