Climate change-induced droughts have far-reaching consequences, including water scarcity and reduced agricultural yields, while also impacting the balance and resilience of socio-ecological systems. Typically, stakeholders in the food, energy, and water (FEW) sectors develop individual adaptation plans, failing to consider the interconnectedness of these systems and the full range of benefits each sector could receive. In Umatilla River Basin (URB), previous studies have shown that the lack of coordination in adaptation planning between these sectors could lead to a decline in the resilience of the region and an increase in regime shifts in natural components (i.e., snowmelt and groundwater recharge) due to projected droughts. In response to these findings, stakeholders in URB are considering the replacement of certified groundwater rights with Columbia River water as a long-term drought mitigation strategy. The goal of this study was to evaluate the long-term impacts different drought mitigation strategies could have on the long-term resilience of the region by using a list of resilience indicators (e.g., extreme drought frequency, groundwater recharge, agricultural yields, etc.) and multidisciplinary design analysis and optimization (MDAO) framework. The MDAO optimization framework allowed for adaptation decisions to evolve over time, based on feedback from actors at various levels while considering the interactions between different actors and their influence on the resilience indicators. Results from this study demonstrate how the proposed approach could help improve the coordination between the FEW sectors and lead to more positive long-term impacts on the resilience of the region in the face of drought-related challenges.