The present study investigated the protective effect of Pyropia yezoensis glycoprotein (PYGP) against chronic ethanol consumption‑mediated hepatotoxicity in rats. Male Sprague-Dawley rats (n=20; 6 weeks old) were randomly divided into four groups. The rats in each group were treated for 30 days with the following: i) CON group, distilled water only; ii) EtOH group, 20% ethanol 3.7 g/kg/BW; iii) EtOH+150 group, 20% ethanol 3.7 g/kg/BW+PYGP 150 mg/kg/BW; iv) EtOH+300 group, 20% ethanol 3.7 g/kg/BW+PYGP 300 mg/kg/BW. EtOH, PYGP and water were orally administered. The rats were sacrificed after 30 days, and blood and liver samples were collected for analysis. Treatment with ethanol caused significant elevation of serum levels of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT). Furthermore, inhibition of the antioxidant defense system in the liver, including glutathione (GSH), glutathione peroxidase (GSH‑px) and catalase (CAT) was observed. However, co‑administration with PYGP recovered the antioxidant defense system, and the serum levels of GOT and GPT. PYGP was shown to attenuate ethanol toxicity via the inactivation of mitogen‑activated protein kinases (MAKPs). PYGP suppressed the overexpression of cytochrome P450 2E1 (CYP2E1), inducible nitric oxide synthase and cyclooxygenase‑2. These results suggested that the protective effect of PYGP was associated with antioxidant activities, MAPKs and the CYP2E1 signaling pathway.