Enzymatic degradation of elastin by matrix metalloproteinases (MMPs) leads to the permanent dilation of aortic wall and constitutes the most prominent characters of aortic aneurysm and aging-related medial degeneration. Hydrogen sulfide (HS) as a gasotransmitter exhibits a wide variety of cardio-protective functions through its anti-inflammatory and anti-oxidative actions. Cystathionine gamma-lyase (CSE) is a main HS-generating enzyme in cardiovascular system. The regulatory roles of CSE/HS system on elastin homeostasis and blood vessel degeneration have not yet been explored. Here we found that aged CSE knockout mice had severe aortic dilation and elastic degradation in abdominal aorta and were more sensitive to angiotensin II-induced aortic elastolysis and medial degeneration. Administration of NaHS would protect the mice from angiotensin II-induced inflammation, gelatinolytic activity, elastin fragmentation, and aortic dilation. In addition, human aortic aneurysm samples had higher inflammatory infiltration and lower expression of CSE. In cultured smooth muscle cells (SMCs), TNFα-induced MMP2/9 hyperactivity and elastolysis could be attenuated by exogenously applied NaHS or CSE overexpression while further deteriorated by complete knockout of CSE. It was further found that HS inhibited MMP2 transcription by posttranslational modification of Sp1 via S-sulfhydration. HS also directly suppressed MMP hyperactivity by S-sulfhydrating the cysteine switch motif. Taken together, this study revealed the involvement of CSE/HS system in the pathogenesis of aortic elastolysis and medial degeneration by maintaining the inactive form of MMPs, suggesting that CSE/HS system can be a target for the prevention of age-related medial degeneration and treatment of aortic aneurysm.