Abstract Transformation of forests into agricultural lands threatens biodiversity and ecosystem functions globally. In the biodiversity hotspot Madagascar, key ecosystem functions along with highly endemic flora and fauna are under threat. Comprehensive studies identifying proximate drivers are lacking, with no studies accounting for endemic species richness across multiple taxa. We assess how plot-scale stand structural attributes (basal area, leaf area index, diameter diversity, and tree species richness) and landscape-scale forest cover affect biodiversity (species richness of butterflies, ants, birds, amphibians, reptiles, herbaceous plants, and multidiversity) and ecosystem functions (soil organic carbon, predation rate, acoustic diversity index, and multifunctionality) in the tropical mosaic landscape of northeastern Madagascar. Across a prevalent land-use gradient in the region, we sampled five woody land-use types: old-growth forest, forest fragment, woody fallow, forest-derived and fallow-derived vanilla agroforests. Complexly structured stands with a larger basal area and higher tree species richness promoted greater endemic multidiversity and certain ecosystem functions. Landscape-scale forest cover significantly favored, particularly, endemic bird species richness. Our models explained 70% of the variance in endemic multidiversity, 26% in multidiversity, and 43% in multifunctionality. Significant effects directions of our predictors differed between taxa but were univocally positive for endemic species richness. Our findings highlight that a simplified stand structure, resulting from land-use change, substantially reduces endemic biodiversity and ecosystem functions in this historically forested region. Conservation actions should aim at maintaining complex stand structure in forests and agroforests, while restoration interventions should focus on re-building such structures.