Abstract: Fishmeal replacement is crucial for promoting sustainable aquaculture, and cottonseed protein concentrate (CPC) is considered a promising plant protein source. Currently, the fishmeal constitutes over 50% of commercial diets for Siniperca chuatsi, highlighting the urgency of reducing its proportion to enhance the sustainability of aquaculture industry. This study investigated the tolerance threshold of S. chuatsi to CPC, as well as its effects on growth performance, feed utilization, liver and intestinal health, and compensatory growth during nutritional recovery. Juvenile S. chuatsi initial weight (34.47±0.07) g were fed isonitrogenous and isolipidic diets with fishmeal replaced by CPC at levels of 0% (CF0), 17.5% (CF17.5), 35.0% (CF35.0), 52.5% (CF52.5), and 70.0% (CF70.0) for six weeks, followed by a six-week nutritional recovery period with the control diet. Results showed S. chuatsi exhibited lower tolerance to CPC than other carnivorous fish species. Despite essential amino acid supplementation, CPC replacement at 17.5% (151.8 g/kg) or higher significantly reduced weight gain and specific growth rates, while increasing feed conversion ratio and protein efficiency ratio (P < 0.05). Growth and metabolism were disrupted, leading to a reduction in whole-body crude lipid content, hepatic Oil Red O staining and gonadosomatic index at all replacement levels of 17.5% or higher, as well as a decrease in perivisceral fat index specifically at the 70% replacement level (P < 0.05). At the transcriptional level, ampk, s6k, gh, igf-1 and lipid metabolism genes (srebp-1, fas, acc1) were significantly upregulated in CF35.0 and CF70.0 (P < 0.05), while npy and pomc exhibited brain-specific downregulation but were concurrently upregulated in CF35.0 and CF70.0 in the midgut (P < 0.05). Liver health declined at 35% replacement, with reduced SOD, CAT, and GPx activities and increased MDA, ALT, and AST levels (P < 0.05), accompanied by p53-mediated hepatocyte apoptosis, suggesting the occurrence of severe liver damage. In contrast, the 70% replacement group exhibited increased SOD, CAT, and GPx activities, decreased MDA, ALT, and AST levels (P < 0.05), and potential compensatory repair through becn1 upregulation and caspase-3 downregulation. CPC replacement also impaired intestinal health, significantly reducing villus height, width, and muscle layer thickness (P < 0.05). Tight junction protein genes (occludin, zo-1) were downregulated (P < 0.05) while nos1 was upregulated (P < 0.05), suggesting increased oxidative stress. Pro-inflammatory cytokines (tnf-α, il-1β) were downregulated (P < 0.05), indicating potential inflammation suppression and immune inhibition. Digestive enzyme activity increased at low replacement levels but declined with further CPC inclusion (P < 0.05). After six weeks of nutritional recovery, weight gain rate, specific growth rate, and protein efficiency linearly increased with prior CPC replacement levels, while the feed conversion ratio decreased linearly (P < 0.05), demonstrating a typical compensatory growth pattern. Villus number, length, width, and muscle layer thickness increased, suggesting improved digestive and absorptive capacity. The CPC35.0 group demonstrated a synthesis-dominant metabolic mode, characterized by the significant upregulation of mtor, igf-1, srebp-1, and fas (P < 0.05), leading to lipid accumulation and vacuolation. In contrast, the CPC70.0 group showed sustained upregulation of mtor/s6k during nutritional recovery (P < 0.05), where as igf-1, srebp-1, and fas returned to control levels (P > 0.05). Meanwhile, pcna and ccnd1 were significantly upregulated (P < 0.05), enhancing hepatocyte proliferation and tissue repair. Reactivated ampk upregulated ppar-α (P < 0.05), promoting fatty acid oxidation and restoring hepatocyte morphology. The hepatosomatic index (HSI) significantly increased (P < 0.05), indicating restored hepatic energy reserves. The study indicated that CPC replacement at 17.5% or higher significantly impacted growth, feed utilization, and liver-intestinal health in S. chuatsi. However, during nutritional recovery, S. chuatsi displayed compensatory growth, with weight gain rate, specific growth rate, and protein efficiency increasing with prior CPC replacement levels. Through metabolic remodeling and energy redistribution, growth and tissue repair were effectively restored. These findings provide insights into CPC as an alternative to fishmeal and its significance in developing precision nutrition strategies for sustainable aquaculture.