Con A-induced hepatitis in mice is an established model of autoimmune hepatitis (AIH). JKB-122, a toll-like receptor 4 (TLR4) antagonist, was tested for hepatotprotectant activity. Within several hours of Con A challenge (15 mg/kg iv), increased production of proinflammatory cytokines with inflammatory infiltrate occurred in the liver. The severity of tissue necrosis and the amount of circulating liver enzymes peak at 24 h post Con A challenge. JKB-122 was given 24 and 16 h before, then concurrently, and 4 and 8 h (× 5 doses) after challenge with Con A. Serum and liver were harvested at 3, 9 and 24 h post Con A challenge. JKB-122 at 20 and 50 mg/kg po prevented the increase of serum liver enzymes by 47% and 95% respectively vs vehicle control 24 h post Con A. JKB-122 significantly inhibited Con A-induced pathological lesions in the liver and the amount of IFN-γ IL-1β, IL-4, IL-5, IL-6, IL-17A and TNF-α starting as early as 3 h post Con A. Moreover, JKB-122 given concurrently (× 3 doses) with Con A showed similar effect. Finally, JKB-122 enhanced the therapeutic effects of submaximal dose of prednisolone with improved lesion score. It is concluded that JKB-122 at 20 and 50 mg/kg po caused dose-dependent inhibition of elevated liver enzymes in Con A-induced hepatitis in mice, indicating hepatoprotectant activity. The results suggest that JKB-122 as monotherapy or in combination with prednisolone may offer a viable approach to the treatment of AIH.