Compelling evidence indicates that oxidative stress contributes to motor neuron injury in amyotrophic lateral sclerosis (ALS), but anti-oxidant therapies have not yet achieved therapeutic benefit in the clinic. The nuclear erythroid 2-related-factor 2 (Nrf2) transcription factor is a key regulator of an important neuroprotective response by driving the expression of multiple cytoprotective genes via its interaction with the anti-oxidant response element (ARE). Dysregulation of the Nrf2-ARE system has been identified in ALS models and the human disease. Taking the Nrf2-ARE pathway as an attractive therapeutic target for neuroprotection in ALS, we aimed to identify CNS penetrating, small molecule activators of Nrf2-mediated transcription in a library of 2000 drugs and natural products. Compounds were screened extensively for Nrf2 activation, anti-oxidant and neuroprotective properties in vitro. S[+]apomorphine, a receptor-inactive enantiomer of the clinically approved dopamine-receptor agonist (R[-]apomorphine), was identified as a non-toxic Nrf2 activating molecule. In vivo S[+]apomorphine demonstrated CNS penetrance, Nrf2 induction and significant attenuation of motor dysfunction in the SOD1(G93A) transgenic mouse model of ALS. S[+] apomorphine also reduced pathological oxidative stress and improved survival following an oxidative insult in fibroblasts from ALS patients. This molecule emerges as a promising candidate for evaluation as a potential neuroprotective agent in ALS patients in the clinic.