Background <p>Nasopharyngeal carcinoma (NPC) is characterized by its aggressive behavior and a pronounced tendency for metastasis. Artesunate (ART), an antimalarial drug, has demonstrated anticancer properties; yet, the underlying mechanisms of its action in NPC are poorly defined.</p> Methods <p>The anti-tumor effects of ART on NPC cells (proliferation, apoptosis, migration, invasion, and angiogenesis) were assessed in vitro. An integrated approach combining network pharmacology (using NPC-related DEGs from dataset GSE118719 and predicted ART targets) and molecular docking identified potential targets. Key findings were validated through qRT-PCR, WB, gelatin zymography, loss/gain-of-function assays, and an in vivo xenograft model.</p> Results <p>ART significantly inhibited NPC cell proliferation, migration, invasion, and angiogenesis, while inducing apoptosis. Network pharmacology identified MMP2 as a core target, and molecular docking confirmed high-affinity binding between ART and MMP2. MMP2 was upregulated in NPC tissues and cells. Knockdown of MMP2 suppressed malignant phenotypes, while its overexpression reversed ART-induced inhibition. In vivo, ART treatment reduced tumor growth and downregulated the expression of MMP2 and Ki67.</p> Conclusion <p>ART exerts potent anti-NPC effects by directly targeting and inhibiting MMP2, highlighting its potential as a therapeutic agent for NPC.</p>