Accumulation of α‑synuclein (α‑SYN) is a common pathology for Parkinson's disease (PD). There is abundant evidence that the toxic‑gain‑of‑function of α‑SYN's is associated with aggregation and consequent effects. To assess the potential of chondroitin sulfate (CS) in this regard, the present study investigated its neuroprotective on SH‑SY5Y cells overexpressing wild‑type (WT) or A53T mutant α‑SYN. Cell viability was measured by MTT assay. Apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential were detected by flow cytometry. The protein expression levels of total α‑SYN, phosphorylated Ser129 α‑SYN, B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax) and cytochrome‑c (Cyt‑c ) were analyzed by western blotting. It was observed that CS reduced the expression levels of total α‑SYN and phosphorylated Ser129 α‑SYN, prevented cell loss and inhibited apoptosis. The subsequent mechanism study indicated that CS inhibited ROS overproduction. CS also significantly attenuated WT and A53T mutant α‑SYN‑induced dysfunction, including decrease of mitochondrial membrane potential, decrease of Bcl‑2 expression, and increase of Bax expression, release of Cyt‑c from the mitochondria and activation of caspase‑3 and caspase‑9, which demonstrated that CS suppressed α‑SYN‑induced apoptosis possibly through mitochondria protection. These results suggested that CS protects SH‑SY5Y cells overexpressing WT or A53T mutant α‑SYN by inhibiting the expression and phosphorylation of α‑SYN, and ROS overproduction and mitochondrial apoptosis. These results implicate CS as a potential therapeutic agent for the treatment of PD.