Hyperomocysteinemia (HHcy) has been associated with mild cognitive impairment and dementia. Hydrogen sulfide (H S) has been suggested to be an endogenous modulator of neuronal functions. However, the effect and mechanisms involved in beneficial effect of H S has not been investigated in homocysteine (Hcy)-induced cognitive deficits. This study has been designed to evaluate the effect of exogenous H S on behavioral deficits and neurochemical alterations in HHcy animals. Hcy levels were significantly elevated in plasma, cortex, and hippocampus of Hcy administered animals. A progressive decline in memory functions and increased anxiolytic behavior was observed in HHcy animals. This was accompanied by decrease in endogenous H S levels along with decreased activity of cystathionase (CSE) and cystathionine β-synthase (CBS). However, a significant increase in CSE and CBS mRNAs was observed. In addition, the catecholamine and serotonin levels were reduced and the activity of monoamine oxidase A and B were increased in brain regions of HHcy animals. Haematoxylin and eosin staining revealed higher number of pyknotic cells in brain regions of HHcy animals. H S administration was found to lower elevated plasma and brain Hcy levels. The activities of CBS, CSE, and levels of H S were restored in HHcy animals administered H S. Exogenous H S also ameliorated behavioral deficits accompanied by significant increase in catecholamines. Histological analysis revealed normal cell morphology in Hcy-treated animals supplemented with H S. These results clearly demonstrate that the protective effect of H S on Hcy-induced cognitive deficits is mediated through increased catecholamine and H S levels thereby suggesting its beneficial role in preventing HHcy-induced neurodegeneration. © 2016 BioFactors, 43(3):434-450, 2017.