This study investigated the effects of replacing dietary fish meal (FM) with Clostridium autoethanogenum protein (CAP) on growth, nutritional metabolism, and immunity in spotted sea bass (Lateolabrax maculatus). Five isonitrogenous and isolipidic diets were formulated to replace 0% (HF), 15%, 30%, 45%, and 60% of FM with CAP. Juveniles (initial weight 65.45 ± 0.5 g) were fed the experimental diets for 8 weeks. Results showed that growth performance was significantly impaired at higher replacement levels. Fish fed diets with 45% and 60% FM replacement exhibited lower weight gain rate, specific growth rate, and protein efficiency ratio, along with higher feed conversion ratio (P < 0.05). Antioxidant capacity was compromised at 60% replacement, evidenced by decreased total superoxide dismutase and catalase activities and increased malondialdehyde content in the liver. Altered activities of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase indicated hepatic stress. Immune responses showed tissue-specific patterns: hepatic toll-like receptor 1 was downregulated in high replacement groups, while intestinal immune genes (interleukin-4, toll-like receptor 1, toll-like receptor 2, and p38 mitogen-activated protein kinase) were upregulated. Lipid metabolism genes showed downregulation of lipogenic genes and upregulation of lipolytic genes. Histopathological examination confirmed hepatocyte vacuolization and nuclear migration at 45% and 60% replacement, with the thinnest intestinal muscular layer at 60% replacement. In conclusion, replaced 30% FM with CAP did not affect the growth and health of sea bass, but further replacement caused growth suppression, hepatointestinal damage, oxidative stress, and immunometabolic dysregulation (P < 0.05).