Populations of wild spring-run Chinook salmon in California’s Central Valley, once numbering in the millions, have dramatically declined to record low numbers. Dam construction, habitat degradation, and altered flow regimes have all contributed to depress populations, which currently persist in only a few tributaries to the Sacramento River. Mill Creek (Tehama County) continues to support these threatened fish, and contains some of the most pristine spawning and rearing habitat available in the Central Valley. Despite this pristine habitat, the number of Chinook salmon returning to spawn has declined to record low numbers, likely due to poor outmigration survival rates. From 2013-2017, 334 smolts were captured and acoustic tagged while out-migrating from Mill Creek, allowing for movement and survival rates to be tracked over 250 kilometers through the Sacramento River. During this study California experienced both a historic drought and record rainfall, resulting in dramatic fluctuations in year-to-year river flow and water temperature. Cumulative survival of tagged smolts from Mill Creek through the Sacramento River was 9.5% (±1.6) during the study, with relatively low survival during historic drought conditions in 2015 (4.9% ± 1.6) followed by increased survival during high flows in 2017 (42.3% ± 9.1). Survival in Mill Creek and the Sacramento River was modeled over a range of flow values, which indicated that higher flows in each region result in increased survival rates. Survival estimates gathered in this study can help focus management and restoration actions over a relatively long migration corridor to specific regions of low survival, and provide guidance for management actions in the Sacramento River aimed at restoring populations of threatened Central Valley spring-run Chinook salmon.