--- - |2- Our findings demonstrated that circular homeodomain interacting protein kinase 3 (circHIPK3) facilitated nasopharyngeal carcinoma (NPC) progression through protecting E74‐like ETS transcription factor 3 (ELF3) from microRNA (miR)‐4288‐mediated silencing, which suggested that the circHIPK3‐miR‐4288‐ELF3 regulatory loop might be a potential target for NPC prevention. Circular RNAs (circRNAs) are reported to regulate the development and progression of multiple cancers. However, the functions of circRNAs in nasopharyngeal carcinoma (NPC) are unclear. In this study, we identified that circular homeodomain interacting protein kinase 3 (circHIPK3) was highly expressed in NPC tissues and cell lines. Moreover, we found that circHIPK3 expression levels could act as a prognostic marker in NPC patients. We showed that circHIPK3 silence repressed NPC cell proliferation, migration, and invasion in vitro. In addition, circHIPK3 depletion dramatically repressed tumor growth and metastasis in vivo. Mechanistically, we revealed circHIPK3 as a competing endogenous RNA of microRNA (miR)‐4288 that targets E74‐like ETS transcription factor 3 (ELF3) in NPC cells. We found that miR‐4288 inhibition reversed the effects of circHIPK3 silence on NPC cells. Furthermore, rescue assays also indicated that circHIPK3 promoted the malignant behaviors of NPC cells via enhancing ELF3 expression by suppressing the miR‐4288 levels. In conclusion, our findings demonstrated that circHIPK3 facilitated NPC progression through protecting ELF3 from miR‐4288‐mediated silencing, which suggested that the circHIPK3‐miR‐4288‐ELF3 regulatory loop might be a potential target for NPC prevention. - 'Journal of Cellular Physiology, Volume 234, Issue 2, Page 1699-1706, February 2019. '