The inhibition of hepatic stellate cell (HSC) proliferation has been considered as an effective therapeutic target for the treatment of liver fibrosis. The methanolic extract of Liriodendron tulipifera showed significant inhibitory activity against the proliferation of HSCs. Bioactivity-guided isolation afforded twelve compounds including (−)-sesamin (1), (−)-syringaresinol (2), (+)-dihydrodehydrodiconiferyl alcohol (3), salvinal (4), (+)-guaiacylglycerol-8-O-4′-dihydroconiferyl ether (5), (±)-guaiacylglycerol-8-O-4′-sinapyl alcohol ether (6), tanegool (7), (+)-5,5′-dimethoxy-7-oxolariciresinol (8), 3-hydroxy-4-methoxyacetophenone (9), 4-acetoxymethylphenol (10), (−)-paramicholide (11), and blumenol A (12). Among the compounds isolated, 2, 3 and 4 significantly attenuated the proliferation of the activated HSC-T6 cells. The maximal dose of these compounds, however, showed no cytotoxicity in primary cultured rat hepatocytes. Collagen deposition in the activated HSC-T6 cells was reduced by 2, 3 and 4. Also, the increased production of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α induced by lipopolysaccharide was decreased by 3 and 4 in RAW264.7 macrophage cells. Collectively, (−)-syringaresinol (2), (+)-dihydrodehydrodiconiferyl alcohol (3), and salvinal (4) isolated from L. tulipifera leaves and twigs exhibited selective antifibrotic activities toward the activated HSCs and suppressed TNF-α production in RAW264.7 macrophages. These compounds may be useful candidates for developing therapeutic agents for the prevention and treatment of hepatic fibrosis.