Unraveling the biotic and abiotic drivers likely influencing clades' diversification dynamics (differential speciation and extinction rates) is crucial for understanding life on Earth. Here, we present a comprehensive analysis of the diversification dynamics of notoungulates (Mammalia: Notoungulata), the most diverse and widespread Cenozoic herbivore mammals that evolved in South America (SA) but are now entirely extinct. Employing fossil occurrences restricted to the southern part of the SA and a Bayesian framework, we examined the historical speciation and extinction rates across all notoungulates, suborders, and three body size categories and tested whether these dynamics could be driven by biotic (e.g., diversity dependence, competition) and abiotic (e.g., Andean uplift and temperature changes) factors. Our findings reveal significant variability in diversification rates over time and groups driven by biotic and abiotic factors. We observed an increase in notoungulate speciation rates correlated with lower group self-diversity, likely related to limited environmental productivity and more extensive emerged continental areas that can provide increased environmental and ecological heterogeneity. In contrast, elevated extinction rates were correlated with intensified Andean uplift events, which can trigger landscape modifications and the arrival of placental carnivores after the Great American Biotic Interchange, probably due to notoungulate vulnerability to novel predation pressures. Furthermore, sparassodont diversity appears to increase speciation and extinction rates of notoungulates, although the direct mechanism relating them remains uncertain. The heterogeneity in the observed patterns of speciation and extinction across distinct size categories and taxonomic clades provides valuable perspectives on how ancient global and regional changes impacted the diversification dynamics of mammals and underscores the intricate interplay between environmental changes and biological interactions in shaping the evolution of life on Earth. (c) 2024 International Association for Gondwana Research. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.