Introduction: Germacrone is a natural product isolated from Rhizoma curcuma with anti-tumor, anti-inflammatory, and anti-bacterial properties. Previous studies have demonstrated that Germacrone exhibits anti-tumor effect in breast and hepatoma cancer cell lines but the studies of its molecular mechanisms and anti-tumor properties in other cancers are not well studied. This study aims to investigate the anti-tumor effect of Germacrone on human skin, cervix, and gastric cancer cell lines and the molecular mechanism underlying the anti-tumor effect of Germacrone. Methods: A375 (skin malignant melanoma), AGS (gastric adenocarcinoma), and HeLa 229 (cervix adenocarcinoma) cell lines were employed for this research. Treatment of the cell lines with Germacrone has inhibited the cell proliferation in a dose-dependent manner as assessed by MTT assay. The cell lines were incubated with Germacrone for 24 hours followed by detection of the expression of BAX, BAK, p53, BCL2, MCL1, and BCL-XL using Real-time PCR. Results: Results from Real-time PCR has showed that pro-apoptotic gene BAK was highly expressed in all the human cell lines after the treatment with Germacrone. Furthermore, the expression of pro-apoptotic gene p53 were elevated in both A375 and HeLa 229 cell lines but not inAGS cell lines. The expression level of pro-survival genes BCL2 and MCL1 were found to be decreased in both AGS and A375 cell lines. Conclusion: In conclusion, Germacrone might be a potent anti-tumor drug candidate for Human Melanoma, Cervix Adenocarcinoma, and Gastric Adenocarcinoma by increasing the expression level of pro-apoptotic proteins BAK. Future studies will focus on studying the cytotoxicity effect of combination of Germacrone with standard chemotherapy drugs on Human Melanoma, Cervix Adenocarcinoma, and Gastric Adenocarcinoma.