Objective We aimed at studying the role of the most deregulated miR‐99a, identifying its downstream targets, and exploring the clinical potential of miR‐99a and its target(s) in oral cancer. Subjects and Methods Following confirmation of miR‐99a deregulation in nine oral lines and 26 pairwise clinical specimens, miR‐99a‐manipulated oral cancer cells were subjected to cell proliferation, migration, invasion, and in vivo murine metastasis assays. We characterized putative miR‐99a target(s) using luciferase reporter assays and genetic manipulation. The inverse relation of miR‐99a and its target(s) was examined in clinical specimens using real‐time PCR and Western blot analysis. Results MiR‐99a down‐regulation was confirmed both in tested oral cancer cell lines and clinical specimens. Ectopic miR‐99a expression inhibited oral cancer cell migration and invasion. Anti‐miR‐99a, silencing miR‐99a functions, had the opposite effect. Myotubularin‐related protein 3 (MTMR3) with one evolutionarily conserved seed region in the 3′‐untranslated region was a novel miR‐99a target. Depleting MTMR3 expression significantly reduced cell proliferation, migration, or invasion. There was an inverse expression of miR‐99a and MTMR3 protein in oral cancer lines and clinical specimens. Conclusion miR‐99a repressed oral cancer cell migration and invasion partly through decreasing MTMR3 expression. MTMR3 may serve as a therapeutic target for oral cancer treatment.