Serenoa repens, the extract of berry in Southeastern United States, is one of several phytotherapeutic agents available for the treatment of Benign prostatic hyperplasia (BPH). In this study, we found for the first time that Serenoa repens effectively inhibited the growth of human U87 and U251 glioma cells. Flow cytometry assay showed that Serenoa repens induced apoptosis of U87 and U251 glioma cells in a dose-dependent manner. Also, Serenoa repens increased the expression of cleaved-PARP, Caspase-3 or p27 protein in these two cell lines, respectively. In addition, we found that Serenoa repens down-regulated basal level of phosphorylated form of signal transducer and activator of transcription 3 (STAT 3) in both U87 and U251 glioma cells. Furthermore, it was discovered that a Janus family of tyrosine kinase (JAK) inhibitor AG490 inhibit the growth of human U87 and U251 glioma cells and AG490 enhanced the ability of Serenoa repens to inhibit the growth of U87 and U251 glioma cells as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. These results indicate that Serenoa repens reduces the growth, causes apoptosis of Glioma cells and inhibits STAT 3 signaling. In addition, it might also be useful for the treatment of individuals with glioma.