Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (HS) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic HS production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic HS production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the HS-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of HS production by GH. Mice lacking CGL failed to downregulate systemic T metabolism and circulating IGF-1, revealing an essential role for HS in the regulation of key longevity-associated hormones.