As part of the Snake River Sockeye Salmon Oncorhynchus nerka recovery effort, a dedicated smolt rearing facility was constructed in 2013 near Springfield, Idaho. In‐hatchery performance and survival were typical for the species, but unexpectedly high mortality rates were observed in the first cohorts of Springfield‐reared smolts upon release into Redfish Lake Creek (RFLC) and during out‐migration. In response, a series of iterative experiments was conducted to identify the cause of the morbidity and mortality observed and to test a range of strategies to mitigate effects on postrelease survival. In the search for possible contributing factors, a difference in water chemistry was noted: whereas Springfield Hatchery's water source is “hard” and has high calcium concentrations, water at the RFLC release site is “soft” and has very low calcium concentrations. In both manipulative experiments and field evaluations, we demonstrated that juvenile Snake River Sockeye Salmon are profoundly affected by instantaneous transitions from high‐ to low‐hardness water. Furthermore, we established a causal link between differences in water chemistry, the associated physiological stress, and morbidity/mortality observed during smolt releases and subsequent out‐migration. A variety of mitigation strategies, including water mixing and water softening, was tested, but stepwise acclimation from high‐ to medium‐hardness water and then from medium‐ to low‐hardness water proved to be the most biologically and logistically effective means of addressing the identified water chemistry differences. Estimates of postrelease survival to Lower Granite Dam (~430 river kilometers downstream) indicated significantly higher survival for acclimated groups (68.7–75.5%) compared to smolts directly released into RFLC (18.1%). Although Snake River Sockeye Salmon smolt survival rates will undoubtedly fluctuate annually with environmental conditions, it is clear that the elevated morbidity and mortality observed in previous years can be addressed through proper acclimation of smolts prior to release.