N-Myc is among the most commonly deregulated oncogenes observed in human cancers and is often linked with high-risk and aggressive cancers. Patients with N-Myc amplified neuroblastoma have a low survival rate and a poor prognostic outcome. N-Myc amplification thus plays a significant role in neuroblastoma onset and tumor progression. Targeting N-Myc would present a promising therapeutic approach but direct targeting of N-Myc is challenging and this molecule has often been termed as “undruggable”. These challenges arise due to various structural and functional properties of N-Myc, making it difficult to target. The aim of the present study was to overcome this challenge and identify inhibitors which could indirectly and potently target N-Myc in N-Myc amplified neuroblastoma. In this study, small molecule inhibitor library was screened for compounds that inhibit proliferation of N-Myc-expression of neuroblastoma cell lines and destabilize N-Myc. Our lab screened a library of 1126 small molecule inhibitors in SHEP WT and SHEP Mutant cell lines. Here, 41 inhibitor hits from the primary screen which were potently inhibiting SHEP WT and SHEP MUT cell lines were validated in a follow up secondary screen. The results from secondary screen did not indicate differential inhibition, as potent and relatively equal inhibition was observed in both the cell lines. However, we identified two small molecule inhibitors involved in indirect destabilization of N-Myc in neuroblastoma cell lines. An IKKα inhibitor, Bardoxolone methyl targeted NFKB expression which resulted in downregulation of NMyc. The second inhibitor, Pacritinib, a selective inhibitor of JAK2 and FLT3 also potently inhibited the proliferation of N-Myc amplified Neuroblastoma cell lines. It was further determined that Bardoxolone methyl and Pacritinib both downregulated reactive oxygen species (ROS) levels in N-Myc amplified neuroblastoma cell lines which resulted in cell death. This identification of novel small inhibitor compounds for the treatment of neuroblastoma via N-Myc destabilization aimed to provide diverse therapeutic agents that target various aspects of N-Myc oncogenicity in neuroblastoma and provide better prognostic outcomes for patients.