Systemic sclerosis can affect multiple internal organs, including the liver and lungs. Nintedanib, an antifibrotic approved for treatment of interstitial lung disease associated with systemic sclerosis, may have activity outside of the lungs. This study explored the effect of preventive and therapeutic nintedanib treatment in a 3-week carbon tetrachloride (CCL₄)-induced (500 mg/kg/day twice weekly for 3 weeks) model of hepatic inflammation and fibrosis in C57Bl/6 mice (aged 8 weeks, n=5 per group). Mice also received nintedanib (30 or 60 mg/kg/day) either each day for 21 days (preventive treatment) or from day 7 or day 14 (therapeutic treatment). Preventive nintedanib treatment at both doses significantly reduced CCL₄-induced increases in myeloperoxidase (p<0.01), hepatic collagen (p<0.001), and interleukin (IL)-6 (p<0.01) in the liver. Nintedanib also significantly reduced hepatic necrosis (p<0.01 and p<0.05), inflammation (p<0.001 and p<0.05), fibrosis (p<0.001 and p<0.05) and IL-1β (p<0.05 and p<0.001) at both 30 and 60 mg/kg/day, respectively. Therapeutic treatment with nintedanib at 30 and 60 mg/kg/day significantly reduced CCL₄-induced serum alanine aminotransferase from day 7 (p<0.05 and p<0.001) and day 14 (p<0.01 and p<0.05), respectively. Increases in tissue inhibitor of metalloproteinase-1 were significantly reduced by nintedanib at 60 mg/kg/day from day 7 only (p<0.001), and nintedanib completely blocked elevation of IL-6 and IL-1β levels regardless of dose or start of treatment (p<0.05–p<0.001). In both the preventive and therapeutic treatment schedules of the study, nintedanib treatment was beneficial in attenuating CCL₄-induced pathology and reducing hepatic injury, inflammation, and fibrosis, demonstrating that nintedanib has antifibrotic and anti-inflammatory activity outside of the lungs.