Environmental managers have sought to optimize landscape structure to maintain regional ecosystem health (EH). However, we still lack a full understanding of the effects of changing landscape structure on EH, especially in terms of shorter time scales (e.g., monthly or seasonal scales) and spatial heterogeneity. To address this gap, this study used the vigor-organization-resilience-services (VORS) model to assess the annual and seasonal variation of EH in the Loess Plateau (LP) during 2000–2015, and then applied the geographically weighted regression (GWR) model to investigate the spatial effects of different aspects (i.e., landscape composition and configuration) of the landscape structure change on EH over time. Our results showed that the EH level in the LP from 2000 to 2015 displayed temporal non-stationarity at annual and seasonal scales, and a spatial pattern of decreasing from southeast to northwest. The effects of landscape structure on EH had obvious spatial and temporal heterogeneity, depending on the local landscape composition and configuration. In general, landscape configuration exerted a greater impact on EH than landscape composition apart from Shannon’s diversity index and percentage of forestland area, but the intensity and direction of the impact displayed higher temporally instability and therefore should receive more attention. Furthermore, regulation of the dominant patch size, landscape connectivity and forest spatial spacing is the optimal choice for regional ecosystem management. The results suggest that EH responses to changes in landscape structure in the LP vary by time and place, and that the integrating temporal variation and spatial characteristics can help decision-makers make precise spatial arrangements and temporal adjustments to keep the negative ecological impacts within reasonable limits.