Elevated level of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), is associated with end-stage renal diseases. Hcy metabolizes in the body to produce hydrogen sulfide (H₂S), and studies have demonstrated a protective role of H₂S in end-stage organ failure. However, the role of H₂S in HHcy associated renal diseases is unclear. The present study was aimed to determine the role of H₂S in HHcy associated renal damage. Cystathionine--synthase heterozygous {CBS(+/- )} and wild type (WT, C57BL/6J) mice with 2-kidney (2-K) were used in this study and supplemented with or without NaHS (30 µmole/L, H₂S donor) in the drinking water. To expedite the HHcy associated glomerular damage uninephrectomized (1-K) CBS(+/- ) and 1-K WT mice were also used with or without NaHS supplementation. Plasma Hcy levels were elevated in CBS(+/-) 2-K, 1-K and WT 1-K mice along with increased proteinuria; whereas, plasma levels of H₂S were attenuated in these groups compared to WT 2-K mice. Interestingly, H₂S supplementation increased plasma H₂S level and normalized the urinary protein secretion in the similar groups of animals as above. Increased activity of MMP-2 and -9, and apoptotic cells were observed in the renal cortical tissues of CBS(+/-) 2-K, 1-K and WT 1-K mice; however, H₂S prevented apoptotic cell death and normalized increased MMPs activities. Increased expression of desmin and down regulation of nephrin in the cortical tissue of CBS(+/-) 2-K, 1-K and WT 1-K mice were ameliorated with H₂S supplementation. Additionally, in the kidney tissues of CBS(+/-) 2-K, 1-K and WT 1-K mice increased superoxide (O₂^•-) production and reduced glutathione (GSH)-to-oxidized glutathione (GSSH) ratio were normalized with exogenous H₂S supplementation. These results demonstrate that HHcy associated renal damage is related to decreased endogenous H₂S generation in the body. Additionally, here we demonstrate with evidence that H₂S supplementation prevents HHcy-associated renal damage, in part, through its antioxidant properties.