Nasopharyngeal carcinoma (NPC) is very common in Southeast China, with the characteristics of high aggression and metastasis. Ankyrin repeat domain-containing protein 22 (ANKRD22) contributes to tumor growth in different tumors, but its role in NPC is still unknown. This study set out to address the action of ANKRD22 in the progression of NPC. The ANKRD22 expression was examined by reverse transcription quantitative polymerase chain reaction and western blot. The function of ANKRD22 in the progression of NPC was addressed through Cell Counting Kit-8, flow cytometry, transwell, luciferase, chromatin immunoprecipitation, and western blot assays. Besides, the in vivo role of ANKRD22 in NPC was assessed using immunohistochemistry and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) assays after nude mice were administrated with HK-1 cells transfected with sh-ANKRD22. The ANKRD22 expression was upregulated in NPC, which predicted a poor prognosis in NPC patients. Knockdown of ANKRD22 suppressed growth and invasion, but enhanced apoptosis in NPC cells. Mechanically, MYC-associated zinc finger protein (MAZ) was a transcription factor of ANKRD22 that positively modulated the ANKRD22 expression in NPC cells. MAZ/ANKRD22 axis accelerated proliferation and invasion, but repressed apoptosis in NPC cells. In vivo, silencing of ANKRD22 diminished the tumor size and weight, the expression of Ki-67 and ANKRD22, but increased apoptosis of NPC. ANKRD22 was transcriptionally modulated by MAZ, which promoted proliferation and invasion, but suppressed apoptosis of NPC.