Evidence highlights the potential role of hydrogen sulfide (H₂S)-donors in preventing vascular dysfunction by modulating pathways associated with oxidative stress. We investigate the H₂S-donor Erucin for its potential to reduce oxidative stress and endothelial dysfunction in obesity. Patients undergoing laparoscopic surgery were categorized by body mass index in controls and patients with obesity. Microvascular endothelial function was measured by micromyography before and after incubation with Erucin 1 µM. Mitochondrial reactive oxygen species (mtROS) were assessed by fluorescence microscopy. Expression of sirtuin 1 (SIRT1) and p66^Shc was detected by real-time PCR. Human vascular endothelial (HUVECs) and smooth muscle cells (HASMCs) were used to study the protective effects of Erucin against H₂O₂-induced oxidative stress, with or without the sirtuin inhibitor Sirtinol. mtROS were assessed in HUVECs, and SIRT1, p66^Shc, and eNOS expression were analyzed via RT-PCR, Western blot, and ELISA. Erucin improved endothelium-dependent vasodilation in arterioles from obese patients, but not in vessels from healthy volunteers, and protected against H₂O₂-induced endothelial damage in vitro. It protected human microvessels from oxidative stress via the NO-SIRT1-p66^Shc pathway, reducing ROS production and upregulating eNOS and SIRT1 while downregulating p66^Shc in endothelial cells. Erucin prevented ROS production in human vascular cells and attenuated endothelial dysfunction related to oxidative stress in vessels of patients with obesity. In conclusion, therapeutic targeting of SIRT1 with Erucin offers a promising strategy to prevent and treat microvascular dysfunction associated with cardiometabolic disorders.