Uric acid is a major antioxidant in the blood of humans that can protect cultured neurons against oxidative and metabolic insults. However, uric acid has a very low solubility which compromises its potential clinical use for neurodegenerative disorders. Here we describe the synthesis, characterization and preclinical development of neuroprotective methyl- and sulfur-containing analogs of uric acid with increased solubility. In vitro and cell culture screening identified 1,7-dimethyluric acid (mUA2) and 6,8-dithiouric acid (sUA2) as two analogs with high antioxidant and neuroprotective activities. When administered intravenously in mice, uric acid analogs mUA2 and sUA2 lessened damage to the brain and improved functional outcome in an ischemia-reperfusion mouse model of stroke. Analogs sUA2 and mUA2 were also effective in reducing damage to the cerebral cortex when administered up to 4 h after stroke onset in a permanent middle cerebral artery occlusion mouse model. These findings suggest a therapeutic potential for soluble analogs of uric acid in the treatment of stroke and related neurodegenerative conditions.