The COVID-19 pandemic has brought profound social, political, economic, and environmental challenges to the world. The virus may have emerged from wildlife reservoirs linked to environmental disruption, was transmitted to humans via the wildlife trade, and its spread was facilitated by economic globalization. The pandemic arrived at a time when wildfires, high temperatures, floods, and storms amplified human suffering. These challenges call for a powerful response to COVID-19 that addresses social and economic development, climate change, and biodiversity together, offering an opportunity to bring transformational change to the structure and functioning of the global economy. This biodefense can include a “One Health” approach in all relevant sectors; a greener approach to agriculture that minimizes greenhouse gas emissions and leads to healthier diets; sustainable forms of energy; more effective international environmental agreements; post-COVID development that is equitable and sustainable; and nature-compatible international trade. Restoring and enhancing protected areas as part of devoting 50% of the planet’s land to environmentally sound management that conserves biodiversity would also support adaptation to climate change and limit human contact with zoonotic pathogens. The essential links between human health and well-being, biodiversity, and climate change could inspire a new generation of innovators to provide green solutions to enable humans to live in a healthy balance with nature leading to a long-term resilient future.