There is an urgent need to identify effective neuroprotective therapies for synucleinopathies such as Parkinson’s disease (PD) and Diffuse Lewy Body Dementia (DLB). Recent emergence of genetic forms of PD has facilitated identification of potential targets for therapeutic development. One of the most promising and extensively studied targets has been lysosomal glucocerebrosidase (GCase) in patients with GBA1-linked PD and DLB. These patients exhibit loss of GCase activity in lysosomes which in turn results in downstream neuronal dysfunction. Therefore, chaperoning and/or direct activation of GCase in lysosomes has been postulated as viable therapeutic strategy. Several ongoing therapeutic efforts have focused on chemical chaperones to promote translocation of mutant GCase to the lysosome. We found that wild-type GCase activity is also reduced in sporadic and genetic forms of PD, suggesting that wild-type GCase could serve as promising therapeutic target in synucleinopathies. Therefore, we explored whether activation of wild-type GCase could enhance lysosomal function and rescue downstream pathological phenotypes in dopaminergic neurons from patients with sporadic and familial forms of PD. We identified GCase activator S-181, which was able to increase the activity of wild-type GCase, and partially ameliorated lipid substrate accumulation, lysosomal dysfunction and dopamine oxidation, in both GBA1-linked and non-GBA1-linked PD patient-derived dopaminergic neurons. Our work thus suggests that rescuing GCase activity is sufficient to improve lysosomal function and to reduce accumulation of toxic oxidized dopamine in midbrain neurons. In turn, decreased accumulation of oxidized dopamine resulted in diminished downstream pathogenic effects, including oxidation-mediated modifications of GCase which disrupt its enzymatic activity. We found that this vicious feedback cycle could be interrupted by targeting wild-type GCase with small molecule activators in human DA neurons. Moreover, our in vivo analysis in mice revealed that S-181 could penetrate CNS and enhance wild-type GCase enzyme activity in brain tissue. In sum, these findings point to the relevance of therapeutically targeting GCase across multiple genetic and sporadic synucleinopathies.