The greatest challenges of the Anthropocene are complex and systemic, with causes, interactions and consequences that cascade across a wide range of interdependent, Anthropocene systems (e.g., land use, hydrology, atmosphere, agriculture, climate, energy, transportation, communication, economic, and sociocultural systems). To address these challenges (e.g., climate change, food insecurity, flooding, biodiversity loss), we are developing an evolutionary, system-of-systems modeling and software framework, and associated decision-support system (which focuses on the co-production of knowledge with stakeholders, scenario analysis, decision-making under deep uncertainty, visualization, and adaptive management), to help managers, stakeholders and policy makers evaluate trade-offs and synergies across systems.