MicroRNAs (miRNAs) are small non-coding RNAs involved in posttranscriptional regulation of protein-coding genes in various biological processes. In our preliminary miRNA microarray analysis, miR-375 was identified as the most underexpressed in human oral tumor versus controls. The purpose of this study was to examine the function of miR-375 as a candidate tumor suppressor miRNA in oral cancer. Cancerous inhibitor of PP2A (CIP2A), a guardian of oncoprotein MYC, was identified as a candidate miR-375 target based on bioinformatics. Luciferase assay accompanied with target sequence mutagenesis elucidated five functional miR-375 binding sites clustered in the CIP2A coding sequence close to the C-terminal domain. Overexpression of CIP2A was clearly demonstrated in oral cancers and inverse correlation between miR-375 and CIP2A was observed in the tumors as well as NCI-60 cell lines indicating the potential generalized involvement of the miR-375-CIP2A relationship in many other cancers. Transient transfection of miR-375 in oral cancer cells reduced the expression of CIP2A resulting in decrease of MYC protein levels, leading to reduced proliferation, colony formation, migration, and invasion. Therefore, this study demonstrated that underexpression of a tumor suppressor miR-375 could lead to uncontrolled CIP2A expression and extended the stability of MYC, which contributes to promoting cancerous phenotypes.