Background: The authors aimed to investigate the role of anti–tumor necrosis factor (TNF)–α monoclonal antibody treatment in a mouse model of parenteral nutrition–associated liver disease (PNALD). Methods: C57BL/6J male mice (aged 6–8 weeks) were randomly assigned to 3 groups: parenteral nutrition (PN), PN with anti–TNF‐α monoclonal antibody treatment (PN + mAb), and controls. A central venous catheter was inserted for intravenous infusion of a PN solution (PN and PN + mAb groups) or saline (controls) for 7 days. Liver pathology, hepatic biochemical indicators, and serum TNF‐α concentrations were analyzed. Levels of hepatic bsep, mdr1a/mdr1b, mdr2, and mrp2 mRNA were also evaluated in each group. Results: The PN group showed significant increases in serum transaminase, direct bilirubin, and bile acids relative to the control group (P < .05). Histopathological changes in this group were consistent with early stage cholestasis. The pathological score and serum alanine aminotransferase, total bilirubin, and direct bilirubin levels were improved in the PN + mAb group relative to the PN group (P < .05). The PN group showed significantly lower hepatic bsep, mdr1a/mdr1b, mdr2, and mrp2 mRNA expression than the controls (P < .05), but these were significantly increased compared to the PN group (P < .05). Conclusions: Infliximab administered at a single dose of 5 mg/kg body weight ameliorated the progression of PNALD and improved the expression of hepatic ABC transporter genes. Therefore, anti–TNF‐α monoclonal antibody may be a beneficial therapy for patients with PNALD.