Background: Neuroblastoma (NB) is a frequent pediatric tumor with poor prognosis. The disregulation of the anti-apoptotic protein Bcl-2 is crucial for the tumoral development and chemoresistance. Autophagy is also implicated in tumor cell survival and chemoresistance. The aim of our study was to demonstrate the in vitro and in vivo therapeutic efficiency of GX 15-070, a Bcl-2 inhibitor, used alone and in combination with conventional drugs used in the treatment of NB and hydroxychloroquine (HCQ), a known autophagy inhibitor. Methods: Using 6 NB cell lines, cell viability (MTT) assays were done at progressively increased concentrations of GX 15-070 alone or in combination with cisplatin or with Z-VAD-FMK, a broad-spectrum caspase inhibitor. Apoptosis was tested by evaluating the cleavage of caspase 3 by western blots (WB) and the Annexin V/7-AAD staining studied by FACS. To assess if autophagy was modified by GX 15-070, the cleavage of LC3 protein was tested by WB and cell survival were tested with combination of GX 15-070 and HCQ. To verify the anti-tumor activity in vivo of GX 15-070, orthotopic injections were made on NSG mice treated with GX 15-070 alone and in combination with HCQ. Results: It was observed a high sensitivity of the NB cells to GX 15-070 with increase of cell death and a potential synergistic of this molecule when it’s combined with cisplatin or HCQ. This cell death was due to apoptosis and may also be inhibited by Z-VAD-FMK. GX 15-070 alone or associated to cisplatin increased the autophagy. The in vivo study showed that GX 15-070 treatment used alone or in combination with HCQ significantly decreased the size of the tumor. Conclusions: Our results support the interest of GX 15-070 in the treatment of NB alone or in combination with classical drugs. Our studies also support that activation of apoptosis associated with inhibition of autophagy have a synergistic potential against tumoral progression and must have to be considered in further mechanistic studies for the optimization of more efficient combined therapies in the treatment of NB.