Background <p>Armadillo repeat-containing X-linked 1 (ARMCX1) has been reported to exhibit a suppressive effect in a variety of solid tumors. However, neither its biological role nor its potential mechanism of action has yet been reported in nasopharyngeal carcinoma (NPC).</p> Methods <p>Immunohistochemical staining of an NPC tissue microarray was performed to evaluate the clinicopathologic association between ARMCX1 and NPC patients. The effect of ARMCX1 on the growth, migratory, and invasive capacities of NPC cells was assessed in vitro using colony formation, Cell Counting Kit-8 (CCK-8), 5-ethynyl-2’-deoxyuridine (EdU), scratch, and Transwell assays. A subcutaneous graft tumor model was implemented to investigate the impact of ARMCX1 on the tumor growth of NPC cells in vivo. Western blotting, immunofluorescence staining, and cycloheximide and proteasome inhibitor experiments were employed to investigate the potential molecular mechanisms of ARMCX1 in NPC</p> Results <p>Overexpression of ARMCX1 effectively inhibited the growth, migration, and invasion in NPC cells. Western blotting, co-immunoprecipitation, immunofluorescence, and cycloheximide and proteasome inhibitor experiments revealed that ARMCX1 mediated the β-catenin ubiquitination and degradation via recruiting tripartite motif-containing protein 21 (TRIM21), thereby suppressing cell cycle progression and epithelial–mesenchymal transition. Final rescue assays demonstrated that β-catenin reversed ARMCX1-mediated suppression of NPC cell proliferation, migration, and invasion.</p> Conclusions <p>ARMCX1 attenuates NPC cell proliferation, migration, and invasion by binding β-catenin and promoting its ubiquitination-dependent degradation via TRIM21. Hence, ARMCX1 may serve as a potential molecular target for therapeutic intervention in NPC.</p>