Aim: Karyopherin alpha 4 (KPNA4, importin alpha 3) has been verified to be an oncogene in many cancers. However, its role in papillary thyroid cancer (PTC), the most frequent endocrine malignancy, is still unclear. Materials and methods: KPNA4 expression was analyzed in PTC tissues and cells. The effects of KPNA4 on the proliferation, invasion, and apoptosis of PTC cells were evaluated after overexpression or downregulation of KPNA4. The influence of KPNA4 on NF-kappa B activation was evaluated by nuclear NF-kappa B p65 expression and NF-kappa B-luciferase reporter assays. Moreover, we also explored whether KPNA4 was regulated by miR-548b-3p. Additionally, the roles of miR-548b-3p and KPNA4 were explored in a xenograft mouse model. Key findings: KPNA4 expression was increased in PTC tissues and cells, and its expression was significantly related to patients' clinicopathologic features and overall survival. Overexpression of KPNA4 significantly promoted PTC cell proliferation and invasion, enhanced nuclear p65 expression and augmented NF-kappa B luciferase activity. However, KPNA4 silencing showed opposite effects on the above indexes, and induced apoptosis of PTC cells. KPNA4 was a target of miR-548b-3p, which was downregulated in PTC and inhibited proliferation and invasion, but promoted apoptosis of PTC cells. KPNA4 overexpression abrogated the suppression of miR-548b-3p on the malignant phenotypes of PTC cells. Both miR-548b-3p overexpression and KPNA4 downregulation inhibited tumor growth and Ki-67 expression, elevated numbers of Tunel-positive cells, and deceased nuclear p65 expression in mouse tumor tissues. Significance: KPNA4 was negatively regulated by miR-548b-3p and promoted the development of PTC via activating the NF-kappa B pathway.