Liver fibrosis is the result of an excessive accumulation of extracellular matrix that develops when inflammation and chronic injury form scar tissue in the liver. Toll-like receptor 9 (TLR9) plays a central role in the innate immune response by recognition of pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). This study aimed to show the therapeutic effects of TLR9 antagonist oligonucleotide (ODN) 2088 on liver fibrogenesis. Mice were injected intraperitoneally with carbon tetrachloride (CCl4) or corn oil twice weekly for up to 8 weeks. Mice were also injected with CpG ODN 2088 (50 μg/20 g) daily for the last 4 weeks. At sacrifice, the serum level of liver enzyme activity was measured. Expression of pro-inflammatory and pro-fibrotic biomarkers was analyzed in liver tissue. TLR9 antagonist, CpG ODN 2088, remarkably decreased the haptic inflammation and fibrosis during CCl4 administration. Treatment with CpG ODN 2088 resulted in reduced serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST). That was paralleled with inhibition in the production of intrahepatic inflammatory and fibrotic factors including collagen, α-Smooth Muscle Actin (SMA), Transforming Growth Factor-beta (TGF-β), interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α). Proliferation (Ki-67) and apoptosis (caspase-3) markers were highly suppressed after CpG ODN 2088 administration. Our results indicate that TLR9 antagonist, ODN 2088, showed protective effects against hepatics inflammation and fibrosis in the CCl4-induced fibrosis model. These observations suggest that ODN 2088 can be a potential therapeutic target for liver fibrosis treatment.