Abstract: In this study, we presented the isolation and characterization of eight novel seco-guaianolide sesquiterpenoids ( 1 – 8 ) and two known guaianolide derivatives ( 9 and 10 ), from the aerial part of Achillea alpina L.. Compounds 1 – 3 were identified as guaianolides bearing an oxygen insertion at the 2, 3 position, while compounds 4 – 8 belonged to a group of special 3-nor guaianolide sesquiterpenoids. The structural elucidation of 1 – 8 , including their absolute configurations, were accomplished by a combination of spectroscopic data analysis and quantum electronic circular dichroism (ECD) calculations. To evaluate the potential antidiabetic activity of compounds 1 – 10 , we investigated their effects on glucose consumption in palmitic acid (PA)-mediated HepG2-insulin resistance (IR) cells. Among the tested compounds, compound 7 demonstrated the most pronounced ability to reverse IR. Moreover, a mechanistic investigation revealed that compound 7 exerted its antidiabetic effect by reducing the production of the pro-inflammatory cytokine IL-1β, which was achieved through the suppression of the NLRP3 pathway.