Natural molecules are under intensive study for their potential as preventive and/or adjuvant therapies for neurodegenerative disorders such as Parkinson’s disease (PD). We evaluated the neuroprotective potential of Cucurbitacin E (CuE), a tetracyclic triterpenoid phytosterol extracted from the Ecballium elaterium (Cucurbitaceae), using a known cellular model of PD, NGF-differentiated PC12. In our post-mitotic experimental paradigm, neuronal cells were treated with the parkinsonian toxin 1-methyl-4-phenylpyridinium (MPP+) to provoke significant cellular damage and apoptosis, or with the potent N,N-diethyldithiocarbamate (DDC) to induce superoxide (O2•-) production, and CuE was administered prior and during the neurotoxic treatment. We measured cellular death and reactive oxygen species to evaluate the antioxidant and anti-apoptotic properties of CuE. In addition, we analyzed cellular macroautophagy, a bulk degradation process involving the lysosomal pathway. CuE showed Neuroprotective effects on MPP+ -induced cell death. However, CuE failed to rescue neuronal cells from oxidative stress induced by MPP+ or DDC. Microscopy and Western blot data show an intriguing involvement of CuE in maintaining lysosomal distribution and decreasing autophagy flux. Altogether these data indicate that CuE decreases neuronal death and autophagic flux in a post-mitotic cellular model of PD.