This study was conducted to understand the effects of glycyrrhetinic acid, berberine, and resveratrol on growth and inflammatory signalling in channel catfish fed a high-fat diet (HFD). Fish (average weight, 20 ± 0.15 g) were distributed randomly in 15 tanks (11 fish per tank). Fish were allocated randomly to five experimental diets: (control diet (ND); high-fat diet (HFD); high-fat diet + 0.3 mg/kg glycyrrhetinic acid (HFD + GA); high-fat diet + 50 mg/kg berberine (HFD + B); and high-fat diet + 400 mg/kg resveratrol (HFD + R). Each diet was tested in triplicates for eight weeks. The final body weight (FBW), body weight gain (BWG), specific growth rate (SGR), and condition factor (CF) were significantly lower in fish fed HFD. In contrast, opposite trends were observed in the feed conversion ratio (FCR), hepatosomatic index (HSI), visceralsomatic index (VSI), and mesenteric fat index (MFI). Fish fed HFD showed a higher trend ( P < 0.05 ) in plasma glucose, cortisol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), liver total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL), while opposite trends were found in total protein (TP) and high-density lipoprotein (HDL). These parameters were all enhanced by feeding the additive-supplemented diets. Liver superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), plasma lysozyme (LYM), myeloperoxidase (MPO), alkaline phosphatase (AKP), acid phosphatase (ACP) activities, and immunoglobulin M (IgM) levels were all lower in fish fed HFD as compared to the control group. However, supplementing GA, berberine, and resveratrol restored these parameters to similar levels to the control group. Upregulated gene expression of interleukin 1β (IL-1ß), nitric oxide (NOS), nuclear factor-kappa B (NF-κB), X box-binding protein 1 (XBP1s), coupled with tumour necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), was observed in fish fed HFD, whereas reverse trends were observed in the additive-supplemented groups as compared to the control group. Overall, glycyrrhetinic acid, berberine, and resveratrol could reduce endoplasmic reticulum stress and inflammation and enhance the immune response in channel catfish fed HFD.