The Congo Basin, one of the world’s most biodiverse ecosystems, is experiencing some of the globe’s fastest and most extensive demographic changes and faces accelerating anthropogenic pressures that threaten both ecological and health stability. Rapid deforestation, land conversion, mining, agricultural expansion, and climate change are fundamentally altering ecological systems and increasing the risk of disease emergence. Evidence links land-use change and habitat fragmentation to elevated spillover risk by creating high-contact interfaces among humans, wildlife, and livestock, while forest degradation erodes “landscape immunity.” Climate change further amplifies disease threats by altering host and vector distributions, increasing pathogen shedding, and compounding stress in wildlife. Under current trajectories, biodiversity loss, habitat degradation, and weak health systems across much of the region heighten vulnerability to disease outbreaks and ecological collapse. Species declines among great apes, elephants, and amphibians illustrate how environmental stress and disease interact to drive extinction risk and destabilize ecosystem services. Mining-related mercury contamination, agricultural intensification, and bushmeat hunting continue to degrade ecological integrity and elevate risk of disease emergence. Policy-driven, One Health-based interventions offer pathways to resilience. Primary prevention, integrating wildlife health into Environmental and Social Impact Assessments (ESIAs), National Biodiversity Strategies and Action Plans (NBSAPs), applying the mitigation hierarchy, and embedding health safeguards into mining, agriculture, and infrastructure planning can reduce ecosystem disruption and promote disease resilience. Strengthening surveillance, supporting sustainable livelihoods, and prioritizing high-risk taxa in health monitoring programs can improve early detection. Protecting intact forests, maintaining wildlife corridors, and adopting climate-smart land-use planning are vital to sustain ecological and community health. The Congo Basin’s future depends on aligning conservation, development, and health agendas under a coordinated One Health framework. Proactive investment in prevention, rather than reactive response, will deliver the most effective, equitable, and cost-efficient outcomes for biodiversity conservation, climate mitigation, and pandemic prevention.