As one of the major forms of terrestrial ecosystem change, land cover change (LCC) alters the structure of surface landscape patterns, thereby causing regional eco-environmental responses. Due to limitations in research methods, existing studies have focused more on the overall response between LCC and the eco-environment, and cannot calculate the level change response of eco-environmental quality caused by LCC. Based on the method of spatial data information granulation, this study used a remote sensing ecological index to represent the eco-environmental system and divided the complex eco-environmental system and land system into a simple system composed of spatial information granules, thus simplifying the spatial data calculation. The main contributions of this study are as follows: (1) A computing method of eco-environmental response to LCC based on spatial granular association was proposed, which can spatially identify the main response types of regional LCC; (2) three measures, namely, spatial association support degree, spatial association confidence degree, and spatial association cover degree, were proposed to measure the eco-environmental response of regional LCC from different perspectives; and (3) during 2001–2020, the eco-environmental response to l LCC, namely, the response to degradation caused by shrinking forest area, was not very dramatic in ASEAN (Association of Southeast Asian Nations).