The relationship between nuclear factor I/B (NFIB) and cancer attracts growing research interest. NFIB has diverse and specific roles in tumor progression and invasion. However, the potential effects and functions of this transcription factor in melanoma remain unclear. The present study sought to determine the distinguishing properties of NFIB in melanoma cells. Immunohistochemical examination of the tissues of 15 patients with melanoma indicated that the expression of NFIB was high in melanoma specimens, compared with the benign nevus and normal skin specimens. In addition, the relationship between high NFIB expression and low overall survival rate was assessed. Functional studies demonstrated that NFIB enhanced the malignancy of melanoma, including proliferation, migration and invasion. In addition, NFIB silencing in A375 and A875 cell lines inhibited the process of epithelial-mesenchymal transition (EMT), upregulated E-cadherin and zona occludens-1, but suppressed N-cadherin and vimentin expression. These findings may suggest a new function of NFIB in promoting the migration and invasion of melanoma cells. Therefore, the present study further evalu- ated the association between NFIB and zinc finger protein E-box binding homeobox-1 (ZEB1) in melanoma. Mechanistic experiments revealed that NFIB exerted its roles during EMT by regulating ZEB1. Overall, the present data indicates that NFIB promotes the malignancy of melanoma, particularly EMT, by modulating the ZEB1 axis, such as ZEB2, ATM and CHK1, which may represent a potential molecular therapeutic target in melanoma. © 2021 Spandidos Publications. All rights reserved.