Objective. The purpose of the study is to explore the effect of K5BW12O40, a polyoxometalate (POM), on the apoptosis of A549 cells and its underlying mechanism and to analyze the potential therapeutic effect of K5BW12O40 in non-small-cell lung cancer. Materials and Methods. A549 cells were treated with different concentrations of K5BW12O40 (0 mg/ml, 0.001 mg/ml, 0.01 mg/ml, and 0.1 mg/ml). The proliferation of A549 cells treated with different concentrations of K5BW12O40 was detected by MTT assay (3-(4,5-dimethylthiazol-2-yl)-2 and 5-diphenyl tetrazolium bromide). The apoptosis of A549 cells induced by K5BW12O40 was detected by flow cytometry. Western blot was used to detect the changes in Bax and caspase-3 protein levels in A549 cells induced by K5BW12O40. Results. As the dose of the K5BW12O40 increases, the cell viability of A549 cells gradually decreases. The results of flow cytometry showed that the apoptotic rate of A549 cells increased with the increase of K5BW12O40 concentration. Western blot results showed that the expression of the apoptosis marker protein caspase-3 was increased in the three groups treated with K5BW12O40 whereas the protein level of Bax did not change significantly in A549 cells treated with K5BW12O40. Conclusions. K5BW12O40 increases the apoptotic rate of A549 cells by upregulating caspase-3.