Background. An extensive body of research suggests that brain inflammation and oxidative stress are the underlying causes of Parkinson’s disease (PD), for which no potent therapeutic approach exists to mitigate the degradation of dopamine neurons. Freshwater clams, an ancient health food of Chinese origin, have been documented to exhibit anti-inflammatory and antioxidant effects. We previously reported that freshwater clam extract (FCE) can attenuate astrocytic activation and subsequent proinflammatory cytokine production from substantia nigra in an MPTP-induced PD mouse model. This article provides insight into the potential mechanisms through which FCE regulates neuroinflammation in a glia model of injury. Materials and methods. In total, 1 μg/mL lipopolysaccharide (LPS) and 200 μM rotenone were conducted in primary glial cell cultures to mimic the respective neuroinflammation and oxidative stress during injury-induced glial cell reactivation, which is relevant to the pathological process of PD. Results. FCE markedly reduced LPS-induced neuroinflammation by suppressing NO and TNF-α production and the expression of pro-inflammatory cytokines. In addition, FCE was effective at reducing rotenone-induced toxicity by diminishing ROS production, promoting antioxidant enzymes (SOD, catalase, and GPx) and minimizing the decline in glial-cell-secreted neurotrophic factors (GDNF, BDNF). These impacts ultimately led to a decrease in glial apoptosis. Conclusions. Evidence reveals that FCE is capable of stabilizing reactive glia, as demonstrated by reduced neuroinflammation, oxidative stress, the increased release of neurotrophic factors and the inhibition of apoptosis, which provides therapeutic insight into neurodegenerative diseases, including PD.