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Spatial land use conflicts (SLUCs) are a critical issue worldwide due to the scarcity of land resources and diversified human demand. Despite many time-series studies of SLUCs, comprehensive research on SLUCs and their driving factors over a long period remain limited. This study was conducted in the Pearl River Delta urban agglomeration, Guangdong Province, China. We constructed a landscape ecological risk assessment model to calculate annual SLUC values and analyze their spatiotemporal distribution over 30 years. K-means clustering analysis was used to cluster SLUC values for 1990–2005 and 2006–2020, yielding comprehensive conflict intensity data for each period. The major factors driving the spatial differentiation of SLUCs and their interactions in each period were identified using an optimal parameter-based geographical detector model. The results show that SLUCs varied significantly over time, with an overall decreasing trend and distinct spatial heterogeneity. Comprehensive conflict intensity for each period was characterized by low values in the peripheral regions and high values in central parts of the study area, which tended to decrease from 1990–2005 to 2006–2020. SLUCs were heavily dependent on topographical (slope and elevation) and environmental (normalized difference vegetation index) factors. Socio-economic factors (gross domestic product and population density) were also major contributors to the spatial differentiation of SLUCs. The explanatory power of multiple interacting factors on SLUCs was enhanced compared with that of individual factors. The explanatory power of the driving factors varied, and their interactions decreased over time. The results may facilitate the rational government planning of regional land use and thus effectively mitigate SLUC intensity at the macro level.