Neuroblastoma, a paediatric cancer, accounts for 15% of childhood cancer mortality. Amplification of N-Myc oncogene occurs in 20% of neuroblastoma patients and is considered high risk as it correlates with aggressiveness and poor prognosis. However, the exact mechanism by which N-Myc contributes to this aggressiveness is poorly understood. Whilst, low expression of p120ctn is correlated with metastasis and poor prognosis in many types of cancer, the role of p120ctn in neuroblastoma is poorly understood. In this study, the role of p120ctn and N-Myc in neuroblastoma aggressiveness was investigated by using RNA interference. Knockdown of N-Myc significantly reduced p120ctn mRNA expression suggesting that p120ctn can be a target of N-Myc. Interestingly, knockdown of p120ctn resulted in a novel finding of N-Myc downregulation. Upon knockdown of p120ctn and N-Myc, the proliferation, migration and invasion of neuroblastoma cells were significantly attenuated. A follow up label-free quantitative proteomics analysis revealed that p120ctn knockdown cells underwent mesenchymal-to-epithelial (MET) transition. Confocal microscopy, Western blotting and qPCR analysis confirmed the MET transition upon p120ctn knockdown. Interestingly, confocal microscopy and Western blotting analysis of subcellular fractionation fractions highlighted the nuclear accumulation of β-catenin upon p120ctn knockdown. TOPFLASH assay confirmed the activation of Wnt signalling pathway by β-catenin and up regulation of Wnt target genes including C-Myc was validated by qPCR analysis. Inhibition of Wnt signaling pathway in p120ctn knockdown cells downregulated C-Myc and upregulated N-Myc suggesting the repression of N-Myc by C-Myc. Overall, these findings suggest that p120ctn plays a pivotal role in neuroblastoma aggressiveness by regulating MET and N-Myc expression.