Updated project metadata. Hydrogen sulfide (H2S) is a signaling molecule that regulates essential plant processes, such as autophagy and responses to abiotic stresses. Although there is much information about the processes in which H2S is involved, the mechanism of action of H2S is still unclear. However, the posttranslational modification of cysteine residues, named persulfidation, is the main proposed mechanism. In this study, the role of H2S during drought that allows plant stress adaptation has been analyzed, with the focus on the underlying mechanism. H2S pretreatment before imposing drought on plants significantly improved phenotypic traits and decreased the content of biochemical and molecular drought stress markers. In addition, H2S regulated amino acid metabolism and repressed drought-induced degradation pathways, such as bulk autophagy and protein ubiquitination. The label-free quantitative proteomic analysis of plants growing under control and drought stress identified 887 proteins significantly different persulfidated between both conditions. Bioinformatic analyses revealed that the biological processes most enriched containing the proteins more persulfidated in drought corresponded to cellular response to oxidative stress, and hydrogen peroxide catabolism. In addition, protein degradation, abiotic stress responses, anthocyanin-containing compound biosynthetic process, and flavonoid biosynthesis were highlighted. On the contrary, the most enriched biological process containing proteins with lower levels of persulfidation in drought corresponded to the biosynthetic processes of glucosinolates and chlorophyll. Therefore, our findings emphasize the role of H2S as a promoter of enhanced tolerance to drought, enabling plants to respond more rapidly and efficiently after exposure to drought. Furthermore, the proteomic analysis supports the main role of protein persulfidation as the molecular mechanism of H2S to alleviate ROS accumulation and balance redox homeostasis under drought stress.