Four new trisubstituted tetrahydrofuran lignans, named (−)-sesaminone-rutinoside ( 1 ), (+)-episesaminone-rutinoside ( 2 ) and rabdosiacosides B ( 3 ) and C ( 4 ) were isolated from the air-dried whole herbs of Rabdosia lophanthoides var. gerardiana together with two known compounds, (+)− 1-hydroxypinoresinol-1-β- d -glucoside ( 5 ) and rosmarinic acid ( 6 ). The structures of these new lignans were elucidated by a combination of mass spectrometry, 1D and 2D NMR experiments including distortionless enhancement by polarization transfer, 1 H– 1 H correlation, heteronuclear single quantum coherence, heteronuclear multiple bond correlation, and nuclear Overhauser effect spectroscopies. Both the cell viability and their anti-inflammatory effects of the lignans were further studied. Among them, no significant cytotoxic activity was exhibited. Compound 4 dramatically suppressed LPS-induced nitric oxide release and reduced the release of the pro-inflammatory cytokines TNF-α and IL-6 in a dose-dependent manner. Overall, our findings indicate that compound 4 was noteworthy in reducing LPS-induced inflammatory responses in RAW264.7 macrophages. • Four new lignans were isolated and identified from Rabdosia lophanthoides. • All compounds exhibited no cytotoxic activity. • Rabdosiacoside C ( 4 ) suppressed LPS-induced NO release. • The release of pro-inflammatory cytokines was inhibited by rabdosiacoside C ( 4 ).