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Low levels of stresses cause eustress while high stressful situations result in distress. Female rainbow trout (Oncorhynchus mykiss) was reared under crowded conditions to mimic the stressful environment of intensive fishery production. Trout was stocked for 300 days with initial densities of 4.6 ± 0.02 (final: 31.1 ± 0.62), 6.6 ± 0.03 (final: 40.6 ± 0.77), and 8.6 ± 0.04 (final: 49.3 ± 1.09) kg/m3 as SD1, SD2 and SD3. We assessed molecular, cellular and organismal parameters to understand the flexibility of neuro-endocrine-immune network during stress. Trout with higher initial density (SD3) displayed the slightly activated hypothalamus-pituitary-interrenal (HPI) axis with positively increased antioxidant enzyme activities and anti-inflammatory cytokine transcriptions on day 60 or 120. These results indicated that low level of stress was capable of exerting eustress by activating neuro-endocrine-immune network with beneficial adaptation. Transition from eustress to distress was induced by the increased intensity and duration of crowding stress on day 240 and 300. The prolonged activation of HPI axis resulted in suppressed growth hormone-insulin-like growth factor (GH-IGF) axis, up-regulated cytokine transcriptions and severe reactive oxygen species stress. Stress means reset of neuro-endocrine-immune network with energy expenditure and redistribution. Digestive ability of trout with distress was also inhibited on day 240 and 300, indicating a decreased total energy supplement and energy distribution for functions are not necessary for surviving such as growth and reproduction. Consequently, we observed the dyshomeostasis of energy balance and neuro-endocrine-immune network of trout during long-term crowding conditions. Image 1 • Low levels of crowding stress provided eustress with positive HPI activation. • Eustress stimulate adaptive mechanisms in endocrine and immune network. • Long-term crowded conditions cause distress with negatively prolonged HPI activation. • Distress caused maladaptive mechanisms in endocrine and immune network. [ABSTRACT FROM AUTHOR]