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Land degradation is a widespread environmental challenge that threatens landscape sustainability and regional development; existing land degradation neutrality (LDN) efforts in karst areas do not sufficiently consider the complex associations of soil loss with ecosystem services (ESs) and their spatial determinants, which constrain the efficacy of ecosystem restoration projects (ERPs). To close these gaps, this study conducted in China's southwest karst area explored the simultaneous responses of soil loss and ESs to human interventions and identified their spatial determinants by applying biophysical models and an integrated regression approach, respectively. The results showed that, from 1980 to 2017, ERPs substantially enhanced soil retention (SR) for both sub-catchment and entire region scales, and the soil loss has greatly declined since 1999. Carbon stock (CS) and habitat quality remained relatively stable over the entire region, while precipitation variations resulted in fluctuations in water yield (WY) and aquatic purification (AP). Pairwise correlations demonstrated that WY and AP had a significant synergy (p < 0.0001) across all provinces, while CS and WY presented a negative association for Guangxi and Guizhou provinces. Spatial panel models and geographically weighted regressions determined that environmental, socioeconomic, and landscape variables were the primary spatial determinants of multiple ESs and soil loss, and presented significant spatial heterogeneity and spillover effects. Therefore, SR and other ESs should be closely linked, to concurrently address land degradation and enhance ESs. In ERPs and LDN practices, environmental, socioeconomic, and landscape variables and their external effects should be taken into account to propose targeted, integrated, and efficient policies and strategies to facilitate win–win outcomes and realize regional sustainable development. [ABSTRACT FROM AUTHOR]