Ovarian cancer (OC) has the worst prognosis among all malignancy types in females worldwide according to epidemiological studies in 2017. Although radiotherapy, chemotherapy and surgical treatment are the most common treatment methods, their curative effects are not satisfactory. The present study aimed to examine the role of cluster of differentiation 44 variant 6 (CD44v6) in the molecular mechanism of the proliferation and tumorigenicity of OC cells, and provide a novel target for the clinical treatment of OC. A total of 46 clinical samples were collected, including 24 malignant ovarian tumor tissue samples and 22 benign ovarian tissue samples. Expression of CD44v6 and nuclear factor‑κB (NF‑κB) in these samples was detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemistry. The A2780 OC cell line was used to establish a normal control group, a negative control group and a CD44v6‑small interfering (si) RNA transfection group. The expression of CD44v6 and NF‑κB mRNA was detected in each group by RT‑qPCR. The proliferation, invasion and migration abilities of the cells were then assessed by Transwell and colony formation assays. Additionally, immunofluorescence was used to detect nuclear NF‑κB expression. CD44v6 and NF‑κB mRNA expression levels were significantly increased in malignant ovarian tumor tissues, compared with normal ovarian tissues (P< 0.01), and immunohistochemistry demonstrated similar results. In the CD44v6‑siRNA group, NF‑κB mRNA expression was significantly reduced, compared with the control and negative control (both P< 0.01) groups. Transwell and colony formation assays demonstrated that the migration, invasion and colony formation abilities of OC cells in the CD44v6‑siRNA group were significantly reduced, compared with the control and negative control (both P< 0.01) groups. Immunofluorescence results demonstrated that the expression of NF‑κB in the cytoplasm and nucleus of the CD44v6‑siRNA group was also markedly reduced, compared with the other two groups. In conclusion, CD44v6 may participate in the proliferation of OC cells through activation of the NF‑κB pathway and these observations may provide a novel therapeutic target for the clinical treatment of OC.