Manganese (Mn) is an essential trace element, serving as a cofactor for several enzymes involved in various cellular and biochemical reactions in human body. However, chronic overexposure to Mn from occupational or environmental sources induces a neurological disorder, characterized by psychiatric, cognitive, and motor abnormalities, referred to as manganism. Mn-induced neurotoxicity is known to target astrocytes since these cells preferentially accumulate Mn. Astrocytes are the most abundant non-neuronal glial cells in the brain, and they play a critical role in maintaining the optimal glutamate levels to prevent excitotoxic death. The fine regulation of glutamate in the brain is accomplished by two major glutamate transporters – glutamate transporter-1 (GLT-1) and glutamate aspartate transporter (GLAST) that are predominantly expressed in astrocytes. Excitotoxic neuronal injury has been demonstrated as a critical mechanism involved in Mn neurotoxicity and implicated in the pathological signs of multiple neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Recent evidences also establish that Mn directly deregulates the expression and function of both astrocytic glutamate transporters by decreasing mRNA and protein levels of GLT-1 and GLAST. Herein, we will review the mechanisms of Mn-induced gene regulation of glutamate transporters at the transcriptional level and their role in Mn toxicity.