Acclimations of Oreochromis mossambicus to elevated salinity were conducted with multiple rates of salinity increase and durations of exposure to determine the rate-independent maximum salinity limit and the incipient lethal salinity. Quantitative proteomics of over 3000 gill proteins simultaneously was performed to analyze molecular phenotypes associated with treatments representative of key zones in the salinity-level x duration matrix. For this purpose, a species- and tissue-specific data-independent acquisition (DIA) assay library of MSMS spectra was created. From these DIA data, protein networks representing complex molecular phenotypes associated with salinity acclimation were generated. Organismal performance indicators of salinity tolerance were then correlated with salinity-regulated protein networks. O. mossambicus was determined to have a wide “zone of resistance” from approximately 75g/kg salinity to 120g/kg, which fish survive for a limited period with eventual loss of function. Crossing the critical threshold salinity into the zone of resistance corresponds with blood osmolality increasing beyond 400 mOsm, significantly reduced body condition factor, and cessation of feeding. Gill protein networks impacted at extreme salinity levels both above and below the critical salinity threshold include increased energy metabolism, especially upregulation of electron transport chain proteins, and regulation of specific osmoregulatory proteins. Cytoskeletal, cell adhesion, and extracellular matrix proteins are enriched in regulation network patterns that are sensitive to the critical salinity threshold. Network analysis of these patterns provides deep insight into specific mechanisms of energy homeostasis during salinity stress.