In this study, we employed a panel of cell lines to determine whether p53-dependent cell death in neuroblastoma (NB) cells is caused by apoptotic cellular function, and we further studied the molecular mechanism of apoptosis induced via the p53-dependent pathway. We obtained evidence that a type of p53-dependent stress, doxorubicin (Doxo) administration, causes accumulation of p53 in the nucleus of NB cells and phosphorylation of several serine residues in both Doxo-sensitive and -resistant cell lines. Upregulation of p53-downstream molecules in cells and upregulation of Noxa in the mitochondrial fraction were observed only in Doxo-sensitive NB cells. Significance of Noxa in the Doxo-induced NB cell death was confirmed by Noxa-knockdown experiments. Mitochondrial dysfunction, including cytochrome-c release and membrane potential disregulation, occurred and resulted in the activation of the intrinsic caspase pathway. However, in the Doxo-resistant cells, the accumulation in the nucleus and phosphorylation of p53 did not induce p53-downstream p21(Cip1/Waf1) expression and the Noxa upregulation, resulting in the retention of the mitochondrial homeostasis. Taken together, these findings indicate that the p53 pathway seems to play a crucial role in NB cell death by Noxa regulation in mitochondria, and inhibition of the induction of p53-downstream effectors may regulate drug resistance of NB cells.