A prominent signal of the Anthropocene is the extinction and population reduction of the megabiota-the largest animals and plants on the planet. However, we lack a predictive framework for the sensitivity of megabiota during times of rapid global change and how they impact the functioning of ecosystems and the biosphere. Here, we extend metabolic scaling theory and use global simulation models to demonstrate that (i) megabiota are more prone to extinction due to human land use, hunting, and climate change; (ii) loss of megabiota has a negative impact on ecosystem metabolism and functioning; and (iii) their reduction has and will continue to significantly decrease biosphere functioning. Global simulations show that continued loss of large animals alone could lead to a 44%, 18% and 92% reduction in terrestrial heterotrophic biomass, metabolism, and fertility respectively. Our findings suggest that policies that emphasize the promotion of large trees and animals will have disproportionate impact on biodiversity, ecosystem processes, and climate mitigation.