Eleven new seco-guaianolide sesquiterpenoids (1–11) and two new guaianolide dimers (12 and 13), along with five known guaianolide derivatives were isolated from the aerial part of Achillea alpina L. Compounds 1–3 represented three unique 2,3-oxygen inserted guaianolides and 4–8 were five special 3-nor guaianolide sesquiterpenoids. Compounds 9–11 were three novel 1,10-seco-guaianolides, while 12 and 13 were two novel 1,10-seco-guaianolides involved heterodimeric [4 + 2] adducts. The new structures of 1–13 including their absolute configurations were determined by spectroscopic data analysis, combined with quantum electronic circular dichroism (ECD) calculations. To evaluate the hypoglycemic activity of 1–18, glucose consumption was used to investigate in palmitic acid (PA)-mediated HepG2-insulin resistance (IR) cells, and compound 9 displayed the strongest reversal IR activity. A mechanistic study has revealed that the potential compound 9 appeared to be mediated hypoglycemic activity via inhibition of the ROS/TXNIP/NLRP3/caspase-1 pathway.