Neuroinflammation caused by the secretion of cytokines and chemokines by glial cells can promote the development of neurodegenerative disorders. The aim of this study was to explore the effects of pioglitazone (Pio), a drug that induces release of inflammatory mediators, on cytokine and chemokine secretion in astrocytes stimulated with lipopolysaccharide (LPS) to induce inflammation. Astrocytes obtained from the cerebral cortex of newborn C57BL/6 mice and grown in culture were stimulated with LPS and treated with Pio. Treatment of astrocytes with LPS significantly increased the levels of pro-inflammatory factors nitric oxide (NO), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8, but decreased the level of anti-inflammatory factors IL-4 and IL-10 (p < 0.05) compared to untreated control astrocytes. Pio treatment in LPS-stimulated astrocytes had the opposite effect, inhibiting secretion of NO, TNF-α, IL-1β, IL-6, and IL-8 and enhancing IL-4 and IL-10 secretion (p < 0.05). In addition, Pio treatment suppressed the expression of pro-inflammatory chemokines Ccl20, Mcp-1, and Mip-1α mRNA in astrocytes stimulated with LPS (p < 0.05). These results showed that Pio can inhibit the neuroinflammatory response in LPS-activated astrocytes and this response may result from the regulation of cytokine and chemokine secretion from astrocytes.