Background: Nasopharyngeal carcinoma (NPC), a subclass of neck and head cancers, is the predominant cause of cancer-associated death globally. LncRNA MAGI2-AS3 has been previously reported to be associated with multiple cancers, but its molecular mechanism in NPC has not been fully explained. Hence, the purpose of this study is to identify the role and regulatory mechanism of MAGI2-AS3 in NPC. Methods: Reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB) were employed to examine gene levels. The biologic function of MAGI2-AS3 in NPC was estimated by cell counting, EdU, Transwell, and WB assays. Luciferase reporter and radioimmunoprecipitation (RIP) assays were carried out to determine the combination between miR-218-5p and MAGI2-AS3, GDPD5, and SEC61A1. Results: MAGI2-AS3 is expressed at a high level in NPC cell lines. Moreover, MAGI2-AS3 knockdown-suppressed NPC progression in vitro and in vivo. Furthermore, MAGI2-AS3 functioned as a competing endogenous RNA (ceRNA) by sponging miR-218-5p to increase the expression of GDPD5 in NPC. Importantly, it was found that MAGI2-AS3 regulated NPC progression and cisplatin resistance via modulating GDPD5. In addition, MAGI2-AS3 could also promote the proliferation and migration in NPC cells by regulating SEC61A1. Conclusion: MAGI2-AS3/miR-218-5p/GDPD5/SEC61A1 axis drove cell proliferation, migration, and epithelialmesenchymal transition, and conferred cisplatin resistance in NPC, which may provide a novel insight into the development of NPC.