Change to global climate, including both its progressive character and episodic extremes, constitutes a critical societal challenge. We apply here a framework to analyze Climate-induced Extremes on the Food, Energy, Water System Nexus (C-FEWS), with particular emphasis on the roles and sensitivities of traditionally-engineered (TEI) and nature-based (NBI) infrastructures. The rationale and technical specifications for the overall C-FEWS framework, its component models and supporting datasets are detailed in an accompanying paper (Vörösmarty et al., this issue). We report here on initial results produced by applying this framework in two important macro-regions of the United States (Northeast, NE; Midwest, MW), where major decisions affecting global food production, biofuels, energy security and pollution abatement require critical scientific support. We present the essential FEWS-related hypotheses that organize our work with an overview of the methodologies and experimental designs applied. We report on initial C-FEWS framework results using five emblematic studies that highlight how various combinations of climate sensitivities, TEI-NBI deployments, technology, and environmental management have determined regional FEWS performance over a historical time period (1980–2019). Despite their relative simplicity, these initial scenario experiments yielded important insights. We found that FEWS performance was impacted by climate stress, but the sensitivity was strongly modified by technology choices applied to both ecosystems (e.g., cropland production using new cultivars) and engineered systems (e.g., thermoelectricity from different fuels and cooling types). We tabulated strong legacy effects stemming from decisions on managing NBI (e.g., multi-decade land conversions that limit long-term carbon sequestration). The framework also enabled us to reveal how broad-scale policies aimed at a particular net benefit can result in unintended and potentially negative consequences. For example, tradeoff modeling experiments identified the regional importance of TEI in the form wastewater treatment and NBI via aquatic self-purification. This finding, in turn, could be used to guide potential investments in point and/or non-point source water pollution control. Another example used a reduced complexity model to demonstrate a FEWS tradeoff in the context of water supply, electricity production, and thermal pollution. Such results demonstrated the importance of TEI and NBI in jointly determining historical FEWS performance, their vulnerabilities, and their resilience to extreme climate events. These infrastructures, plus technology and environmental management, constitute the “policy levers” which can actively be engaged to mitigate the challenge of contemporary and future climate change.