It is increasingly evident that many natural compounds isolated from plants provide benefits to human health, either by interacting with important signalling pathways or by modulating the intracellular redox state. Salvia desoleana is a herbaceous perennial shrub that is native to the island of Sardinia in the Mediterranean Sea. The leaves of S. desoleana were subjected to different extraction methods: hydrodistillation, supercritical CO 2 (SCCO 2 ) extraction at 90 bar and 50 °C, and at 250 bar and 40 °C. The latter process produced the highest yields of sclareol (811 μg/mg), over both the SCCO 2 extraction at 90 bar and 50 °C (540 μg/mg) and hydrodistillation (53.8 μg/mg). The SCCO 2 extract obtained at 250 bar and 40 °C was used to investigate its ability to modulate some biological activities, including cytotoxicity, and cytoprotection against H 2 O 2 -induced oxidative stress, on normal (HUVEC) and transformed (ECV304) human endothelial cells. Results indicate a strong antioxidant activity of S. desoleana extract on both cellular models, as shown by the inhibitory effect elicited on both H 2 O 2 -induced ROS generation and cell damage.