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Objective: To explore the repairing effect and underlying mechanism of fucoxanthin on non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet (HFD) in C57BL/6 mice. Methods: Fifty-two C57BL/6 mice were randomly divided into four groups, including one normal group (n = 14) and three experimental groups (n = 38). The normal group was fed a regular diet, and the experimental groups were fed a HFD. After feeding for eight weeks, two animals were selected from the experimental groups for serum biochemical assays and liver histological observation, and the other 36 were divided into three groups (n = 12 each): model, low-dose and high-dose fucoxanthin, which were then administrated with physiological saline or fucoxanthin by gavage once a day for six weeks. Body mass was recorded weekly, and all mice were killed after fasting for 12 h at the end of the 14th week. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), free fatty acid (FFA), adiponectin, and leptin were measured. In addition, the levels of superoxide dismutase (SOD) activity, glutathione (GSH-Px), malondialdehyde (MDA), catalase (CAT), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in liver homogenate were also determined. Furthermore, hepatic histopathological changes were observed under microscope, and the protein expressions of the adenosine 5’-monophosphate-activated protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (Nrf2) and toll-like receptors 4 (TLR4) signaling pathways in liver tissues were detected by Western blot. Results: Compared with the model group, the levels of TC, TG, LDL-C, ALT and AST in the fucoxanthin-treated groups were significantly decreased (P < 0.05), Leptin was decreased, while the levels of HDL-C and adiponectin were significantly increased (P < 0.05). Moreover, the levels of GSH-Px, SOD and CAT in the fucoxanthin-treated groups were significantly increased (P < 0.05), leptin was decreased, while the levels of MDA and inflammatory cytokines were significantly decreased (P < 0.05) compared with the model group. The results of hematoxylin-eosin (H&E) staining, oil red O staining, periodic acid-schiff staining (PAS), and transmission electron microscopy (TEM) showed that the histological structure of the liver in the fucoxanthin-treated groups recovered to almost normal. The results of Western blot showed that fucoxanthin treatment upregulated the protein expression of phosphorylated adenosine 5’-monophosphate-activated protein kinase (p-AMPK), peroxisome proliferators-activated receptor α (PPARα), phosphorylated acetyl-CoA carboxylase (p-ACC), and carnitine acyl transferase 1 (CPT-1) in the AMPK signaling pathway, downregulated the expression of sterol regulatory element binding protein-1c (SREBP-1c) and fatty acid synthase (FAS), inhibited the level of Kelch-like epichlorohydrin-associated protein-1 (Keap-1) in the Keap-1/nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway, increased the expression of Nrf2 and its downstream antioxidant proteins heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutamate cysteine ligase modifier (GCLM), and downregulated the expression of TLR4, myeloid differentiation factor 88 (MyD88), phosphorylated nuclear factor κB inhibitory protein α (p-IκBα), and phosphorylated nuclear factor κB (p65) (p-NF-κB (p65)) in the TLR4 signaling pathway. Conclusion: Fucoxanthin can repair HFD-induced NAFLD in mice through regulating lipid metabolism, reducing oxidative stress and suppressing inflammation.