Background: Cryptotanshinone (CT) is a biologically active compound from the root of Salvia miltiorrhiza that has been reported to induce apoptosis in various cancer cell lines; but, it has not yet been fully explored in human mucoepidermoid carcinoma (MEC). Objective: Here, we demonstrated the apoptotic effects and its related mechanism in MC-3 and YD-15 human MEC cell lines. Materials and Methods: The effects of CT on apoptotic activity were evaluated by cell proliferation assay, Western blotting, 4'-6-diamidino-2-phenylindole staining, reverse transcription-polymerase chain reaction, and luciferase assay. Results: Our data show that CT treatment of MC-3 cells results in anti-proliferative and apoptotic activities in MC-3 and it is accompanied by a decrease in phosphorylation and dimerization of signal transducer and activators of transcription 3 (STAT3). CT decreased the expression levels of myeloid cell leukemia-1 (Mcl-1) and surviving, whereas Bcl-xL expression was not changed. CT clearly regulates survivin protein at a transcriptional level and alters Mcl-1 through proteasome-dependent protein degradation. In addition, CT-induced apoptotic cell death in YD-15, another human MEC cell line, was associated with the inhibition of STAT3 phosphorylation. Conclusion: These data suggest that CT could be a good apoptotic inducer through modification of STAT3 signaling in human MEC cell lines.