Objective To investigate the effect of rosiglitazone on the proliferation and apoptosis of colon cancer cells and the changes in the AKT/GSK3β signaling pathway. Methods Different concentrations of rosiglitazone (20.0 μmol/L, 40.0 μmol/L, 80.0 μmol/L) were used to treat colon cancer HT29 cells and HCT116 cells. Cell proliferation was detected by MTT assay. Annexin V FITC/PI cell death detection kit was used to test the cell apoptosis rate. The expression of apoptotic protein Bcl-2, Bax and Akt, GSK3β were detected by Western blot. Results Different concentrations of rosiglitazone had different effect on the proliferation of colon cancer cells compared with the blank control group, and showed a dose dependence (P< 0.01). With the increase of rosiglitazone dose, the apoptosis-inducing effect was increased dose-dependently (P< 0.01). When the cells were treated with rosiglitazone for 48 h, the expressions of Bcl-2/Bax, p-GSK3β, and p-Akt were significantly decreased compared with the blank control group (P< 0.01), but the expression level of Akt and GSK3β was not significantly different compared with the blank control group (P> 0.05). Conclusions Rosiglitazone significantly induces apoptosis and inhibits the proliferation of HT29 cells. It may be via inhibiting Akt/GSK3β signaling pathway and change the ratio of Bcl-2/Bax.