The extract of plant Shilianhua (SLH, Sinocrassula indica Berge) is a component in a commercial product for control of blood glucose. However, it remains to be investigated whether the SLH extract enhances insulin sensitivity in a model of type 2 diabetes. To address this question, the SLH crude extract was fractionated into four parts on the basis of polarity, and bioactivities of each part were tested in cells. One of the fractions, F100, exhibited a strong activity in the stimulation of glucose consumption in vitro. Glucose consumption was induced significantly by F100 in 3T3-L1 adipocytes, L6 myotubes and H4IIE hepatocytes in the absence of insulin. F100 also increased insulin-stimulated glucose consumption in L6 myotubes and H4IIE hepatocytes. It increased insulin-independent glucose uptake in 3T3-L1 adipocytes and insulin-dependent glucose uptake in L6 cells. The glucose transporter 1 (GLUT1) protein was induced in 3T3-L1 cells and the GLUT4 protein was induced in L6 cells by F100. Mechanism study indicated that F100 induced GSK-3 phosphorylation, which was comparable to that induced by insulin. Additionally, the transcriptional activity of NF-B was inhibited by F100. In Raw264.7 macrophages, mRNA expression of NF-B target genes (TNF- and MCP-1) was suppressed by F100. In KK.Cg-Ay/+ mice, F100 decreased fasting insulin, blood glucose, and improved insulin tolerance significantly. We conclude that the F100 may be a bioactive component in the SLH plant. It promotes glucose metabolism in vitro and in vivo. Inhibition of GSK-3 and NF-B may be the potential mechanism.