Sesquiterpene lactones (SLs) are a class of natural products with diverse structural scaffoldings and biological activities, making them intriguing objects in the fields of pharmaceutical industry, drug development, and pharmacology. Herein, fifteen SLs, including eleven undescribed SLs compounds sauruintones A-K (1-8 and 13-15), were isolated and identified from the aerial parts of Saussurea involucrata. Their structures were characterized by using mass spectrometry, spectroscopic methods, computational calculations, and single crystal X-ray diffraction. The Feature-Based Molecular Network (FBMN) strategy was utilized for the annotation of SLs with their MS/MS fragmentation patterns. Most of the SLs exerted their protective effects against oxidative stress by enhancing the levels of antioxidant enzyme (CAT) and reducing the malondialdehyde (MDA) levels. Among them, compound 12 exhibited potent reactive oxygen species (ROS) inhibitory activities and enhanced the activities of CAT, superoxide dismutase (SOD), and glutathione peroxidase (GSH), and decreased the content of MDA at concentrations of 10-25 μM. Further RT-qPCR assays and western blot analysis revealed it reduced the level of ROS by activating the nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway.