Cancer stem cells (CSCs) are responsible for tumor initiation, relapse, and metastasis. Thus, residual CSCs after chemotherapy may result in poor prognosis for nasopharyngeal carcinoma (NPC). Emerging evidence suggests that differentially expressed microRNAs (miRNAs) regulate genes that carry out important functions in CSCs. Here we investigate the interaction of microRNA-873 (miR-873) with the Zic family member 2 (ZIC2) and the effects on downstream serine-threonine protein kinase (AKT) signaling pathway in CSCs in the context of NPC. Initially, microarray-based gene expression profiling identified ZIC2 as a key differentially expressed gene in NPC, which was subsequently confirmed to be upregulated in clinical NPC tissue samples. NPC cells were subjected to sphere-formation conditions in low-attachment plates, followed by sorting of CD133+ cells, which were selected as NPC stem cells after further characterization of stem cell biomarkers. ZIC2 was then shown to be enriched in NPC stem cells at both mRNA and protein levels. However, loss of ZIC2 was associated with the self-renewal, proliferative and tumorigenic properties of NPC stem cells. Next, miRNAs potentially able to target ZIC2 were predicted by the intersection of mirDIP and TargetScan database results, and miRNA miR-873 was found to be downregulated in NPC tissues in general but especially in NPC stem cells. Upregulation of miR-873 inhibited the stem-like properties and tumorigenicity of NPC stem cells, which was found to take place through downregulation of ZIC2 and disruption of the AKT signaling pathway. Collectively, the results obtained suggest that overexpression of miR-873 could aid NPC tumor suppression through reduction of the malignant potential of CSCs.