Serotonin exerts anti-inflammatory, antioxidant and antiapoptotic effects through 5-HT7 receptors. The present study determined the role of 5-HT7 receptors in glutamate-induced neurotoxicity by using human SH-SY5Y neuroblastoma cells. The cells were pretreated with different concentrations of 5-HT7 receptor agonist LP44 and antagonist SB269970 for 60 min, followed by treatment with glutamate. Cell proliferation was measured using xCELLigence system. Treatment with all the concentrations of LP44 significantly protected the cells from the toxic effects of glutamate after 24, 48 and 72 h. Although 5-HT7 receptor expression was significantly upregulated in glutamate-treated cells, it was downregulated in LP44-pretreated cells. Furthermore, LP44 treatment significantly decreased malondialdehyde levels and increased superoxide dismutase activities and glutathione levels. Moreover, LP44 treatment significantly decreased tumor necrosis factor alpha (TNF-a) levels and inhibited caspase 3 and caspase 9 mRNA expression. In contrast, SB269970 treatment exerted an insignificant effect on oxidative stress, inflammation and apoptosis. These findings suggest that exogenous stimulation of the 54-1T7 receptors may be protective in glutamate-induced neurotoxicity and that 5-HT7 receptor agonists can be used as therapeutic agents for preventing glutamate-induced neurological disorders.