Abstract: Hepatic fibrosis is a pathological response to persistent liver injury, characterized by activation of hepatic stellate cells (HSCs) and excessive extracellular matrix (ECM) deposition. Isoimperatorin (ISOIM), a coumarin derivative isolated from Angelica dahurica, has been reported to possess analgesic and anti-inflammatory properties. This study investigated the hepatoprotective potential of ISOIM and its underlying mechanisms against hepatic fibrosis. C57BL/6J mice were intraperitoneally injected with thioacetamide (TAA, 100−200 mg·kg⁻¹) for 5 weeks and received ISOIM (5 or 8 mg·kg⁻¹) administration. HSCs and LX-2 were stimulated with transforming growth factor-β (TGF-β, 10 nmol·L⁻¹) or conditioned medium from lipopolysaccharide (LPS)-primed THP-1 (LPS-MØ-CM), followed by ISOIM (0.78, 1.56, 3.125 μmol·L⁻¹) treatment. In TAA-induced mice, ISOIM reduced serum transaminases, attenuated ECM deposition and histopathological damage, alleviated inflammatory responses, and decreased hepatocyte apoptosis. In activated HSCs, ISOIM inhibited ECM accumulation, reduced inflammatory cytokine expression and promoted apoptotic signaling. Mechanistically, ISOIM showed a potential interaction with LXRα/β, reduced HMGB1-associated inflammatory signaling, and suppressed activation of the HMGB1/NLRP3 signaling, accompanied by enhanced caspase-3-mediated apoptotic signaling in activated HSCs. These effects were consistent with those of the LXRα/β agonist GW3965 and were markedly attenuated by LXRβ or LXRα silencing. In addition, ISOIM regulated LXRα/β and the HMGB1-NLRP3 axis, reduced α-SMA expression, and promoted apoptotic signaling in LX-2 cultured with LPS-MØ-CM. Collectively, ISOIM exerted hepatoprotective effects by activating LXRα/β, inhibiting HMGB1/NLRP3 signaling, and promoting apoptosis of activated HSCs within the hepatic microenvironment.