Antibiotics are used worldwide to treat diseases in humans and other animals; most of them and their secondary metabolites are discharged into the aquatic environment, posing a serious threat to human health. However, the toxicity of antibiotics on aquatic organisms, especially the effects on the detoxification system and immune system, has not been thoroughly studied. Lycopene (LYC) is a naturally occurring hydrocarbon carotenoid, which has received extensive attention as a potential antioxidant. The aim of this study was to investigate whether LYC alleviates exogenous toxicity in carp induced by sulfamethoxazole (SMZ) and the underlying molecular mechanisms. The grass carp were treated with SMZ (0.3 μg L-1) and/or LYC (10 mg per kg body weight) for 30 days. Indexes, such as hepatic function-related including histopathological changes and biochemical parameters, detoxification system-related including the cytochrome P450 enzyme system and antioxidant system, and immune system-related including inflammatory and apoptosis processes were detected. The results showed that SMZ stress leads to significant pathological damage of the liver and induction of oxidative stress. LYC coadministration recovered the cytochrome p450-1A1 homeostasis and decreased SMZ-induced accumulation of intracellular reactive oxygen species (ROS). Mechanistically, indicators in the innate immune system (such as toll like receptors (TLRs), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and IL-8) and the apoptosis pathway (p53, PUMA, B-cell lymphoma-2 (Bcl-2), BCL2-associated X (Bax), and Caspase-9/3) disclosed adaptive activation under SMZ exposure; these anomalies returned to normal or close-to-normal levels after LYC coadministration. Therefore, LYC dietary supplement possesses liver protective function against exogenous toxic compounds like SMZ, making LYC a functional aquatic feed ingredient for aquiculture.