A complete water shortage mitigation plan which includes water shortage indicators and mitigation measures is essential in adaptive water resources management. Current water shortage triggers used to manage water supply shortages typically recognize only past and current hydrologic conditions and system states, e.g., reservoir storage or water levels. A systematic approach to evaluate the effectiveness of water shortage mitigation measures is often lacked. This study proposes a general framework based on daily simulation-optimization computation scheme to develop water shortage mitigation plan. It includes an innovative simulation-optimization based water shortage trigger framework incorporating both demand and supply side uncertainties to evaluate the state of a water supply system. Stochastically generated demand/supply ensembles were used to simulate system decision variables that were used jointly with past and current hydrologic conditions to prescribe water shortage stages. Each water shortage stage was tied to specific demand and supply side adaptive management actions. A mixed integer programming model optimizing source allocation from surface water harvesting, groundwater production and a desalination plant was then used to minimize operational costs and protect the environment while meeting regional demand. Cumulative mitigation actions were implemented as the system moves progressively to a severe water shortage stage. Retrospective analysis using observed flow and demand in the past decade (2005-2015) was used to vet the approach and demonstrate the advantage of forward looking water shortage trigger development scheme. A combination of mitigation measures is evaluated using stochastic flow and demand in the year 2030, revealing that increased magnitude of groundwater production under severe water shortage situations could be largely (50%) reduced, owing to proactive mitigation actions. The framework was applied to Tampa Bay Water and it has general applications to regional water resources management for utilities across US and beyond.