Cystamine, a small disulfide‐containing chemical, is neuroprotective in a transgenic mouse and a Drosophila model of Huntington's disease (HD) and decreases huntingtin aggregates in an in vitro model of HD. The mechanism of action of cystamine in these models is widely thought to involve inhibition of transglutaminase mediated cross‐linking of mutant huntingtin in the process of aggregate formation/stabilization. In this study we show that cystamine, both in vitro and in a transgenic mouse model of HD (R6/2), increases levels of the cellular antioxidant l‐cysteine. Several oxidative stress markers increase in HD brain. We provide further evidence of oxidative stress in mouse HD by demonstrating compensatory responses in R6/2 HD brains. We found age‐dependent increases in forebrain glutathione (GSH), and increased levels of transcripts coding for proteins involved in GSH synthesis and detoxification pathways, as revealed by quantitative PCR analysis. Given the general importance of oxidative stress as a mediator of neurodegeneration we propose that an increase in brain l‐cysteine levels could be protective in HD. Furthermore, cystamine was dramatically protective against 3‐nitropropionic acid‐induced striatal injury in mice. We suggest that cystamine's neuroprotective effect in HD transgenic mice results from pleiotropic effects that include transglutaminase inhibition and antioxidant activity.