Background: Malus toringoides (Rehd.) Hughes is a traditional Tibetan medicine. It demonstrates significant hypoglycemic and hypolipidemic potential. However, the protective effects of M. toringoides extracts on endothelial cells and the mechanisms that underlie their activity have not yet been reported. Objectives: The aim of the study was to explore the anti-inflammatory effects and cellular mechanisms of extracts of M. toringoides (CBTM-E375) in lipopolysaccharide (LPS)-induced human umbilical vein endothelial cells (HUVECs). Materials and Methods: HUVECs were exposed to LPS, and the level of proinflammatory mediators was measured by enzyme-linked immunosorbent assay. Furthermore, the activation of heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), and mitogen-activated protein kinase (MAPK) was examined by Western blot and immunofluorescence analysis. Results: CBTM-E375 significantly downregulated the levels of inflammatory mediators and upregulated the expression of HO-1 by modulating Nrf2 translocation in HUVECs. The transfection of HO-1 small interfering RNA into HUVECs actively reversed the effects of CBTM-E375 in suppressing the expression of proinflammatory cytokines. Furthermore, MAPK activation in response to LPS was also blocked by CBTM-E375. Conclusion: CBTM-E375 exerts anti-inflammatory effects, possibly by modulating the translocation of Nrf2 and expression of HO-1, and inhibiting the phosphorylation of MAPK signaling pathway.