Childhood neuroblastoma is one of the most common types of extra-cranial cancer affecting children with a clinical spectrum ranging from spontaneous regression to malignant and fatal progression. In order to improve the clinical outcomes of children with high-risk neuroblastoma, it is crucial to understand the tumorigenic mechanisms that govern its malignant behaviors. MYCN proto-oncogene, bHLH transcription factor (MYCN) amplification has been implicated in the malignant, treatment-evasive nature of aggressive, high-risk neuroblastoma. In this study, we used a SILAC approach to compare the proteomic signatures of MYCN-amplified IMR-32 and non-MYCN-amplified SK-N-SH human neuroblastoma cells. Tumorigenic proteins, including fatty-acid binding protein 5 (FABP5), L1-cell adhesion molecule (L1-CAM), baculoviral IAP repeat containing 5 [BIRC5 (survivin)] and high mobility group protein A1 (HMGA1) were found to be significantly upregulated in the IMR-32 compared to the SK-N-SH cells and mapped to highly tumorigenic pathways including, MYC, MYCN, microtubule associated protein Tau (MAPT), E2F transcription factor 1 (E2F1), sterol regulatory element binding transcription factor 1 or 2 (SREBF1/2), hypoxia-inducible factor 1α (HIF-1α), Sp1 transcription factor (SP1) and amyloid precursor protein (APP). The transcriptional knockdown (KD) of MYCN, HMGA1, FABP5 and L1-CAM significantly abrogated the proliferation of the IMR-32 cells at 48 h post transfection. The early apoptotic rates were significantly higher in the IMR-32 cells in which FABP5 and MYCN were knocked down, whereas cellular migration was significantly abrogated with FABP5 and HMGA1 KD compared to the controls. Of note, L1-CAM, HMGA1 and FABP5 KD concomitantly downregulated MYCN protein expression and MYCN KD concomitantly downregulated L1-CAM, HMGA1 and FABP5 protein expression, while survivin protein expression was significantly downregulated by MYCN, HMGA1 and FABP5 KD. In addition, combined L1-CAM and FABP5 KD led to the concomitant downregulation of HMGA1 protein expression. On the whole, our data indicate that this inter-play between MYCN and the highly tumorigenic proteins which are upregulated in the malignant IMR-32 cells may be fueling their aggressive behavior, thereby signifying the importance of combination, multi-modality targeted therapy to eradicate this deadly childhood cancer.