Neuroblastoma, a paediatric cancer, accounts for 15% of childhood cancer mortality. Even though neuroblastoma is an aggressive cancer, the exact mechanisms by which the cells resist treatment is poorly understood. Here, we hypothesise that neuroblastoma cells have high expression of mesenchymal markers and hence could attribute to the aggressive phenotype. P120ctn is downregulated in epithelial cancers and is known to play a major role in EMT and aggressiveness. In this study, immunohistochemical staining of neuroblastoma patient tissues suggested that p120ctn is highly abundant. Hence, the role of p120ctn and N-Myc in neuroblastoma aggressiveness was investigated by using RNA interference. Amplification of N-Myc oncogene occurs in 20% of neuroblastoma patients and is considered high risk as it correlates with aggressiveness and poor prognosis. Interestingly, knockdown of p120ctn down regulated N-Myc both at mRNA and protein levels. Upon knockdown of p120ctn and N-Myc, the proliferation, invasion and migration of neuroblastoma cells were significantly reduced. Quantitative proteomic and qPCR analysis of the wild type and knockdown cells revealed that p120ctn knockdown cells underwent mesenchymal-to-epithelial transition. Confocal microscopy and Western blotting analysis of subcellular fractionation showed nuclear accumulation of β-catenin upon p120ctn knockdown. Once in the nucleus, β-catenin activated Wnt signalling pathway and up regulated Wnt target genes including C-Myc. Interestingly, down regulation of p120ctn sensitized the neuroblastoma cells to doxorubicin. Currently, there is no published study that explores the role of p120ctn in neuroblastoma. However, these findings are contradictory to scientific literature in the context of the functional role of p120ctn in epithelial cancer. Hence to validate our findings, we established knockdown of p120ctn in epithelial colorectal cancer cells. Consistent with the literature, knockdown of p120ctn induced EMT, proliferation and migration. These results suggest that the role of p120ctn is cell type dependent. Overall, the findings from this study suggest that p120ctn plays a pivotal role in progression of neuroblastoma.