The peroxisome proliferator activated receptor gamma co-activator 1 alpha (PGC1α) is an inducible transcriptional co-activator with direct function in the induction of mitochondrial biogenesis. In the present report we show that, in SH-SY5Y neuroblastoma cells, garlic-derived diallyl disulfide (DADS) is able to increase PGC1α expression in a ROS-dependent manner and to induce mitochondrial biogenesis at early stage of treatment that precede cell cycle arrest and apoptosis outcome. In particular, we demonstrate that DADS elicits: i) the increase of PGC1α within nuclear compartment; ii) the decrease of PGC1α non-active acetylated form; iii) the induction of nuclear-encoded mitochondrial genes such as TFAM and TFBM1. We also show an accumulation of PGC1α within mitochondria along with an increased association with the regulatory D-Loop region of mtDNA and a concomitant augmented expression of mitochondrial RNA. Such events are related to a prompt elevation of mitochondrial mass, as assessed by evaluating the content of mtDNA. We show that the induction of mitochondrial biogenesis is directed to dampen the cytotoxic effect of DADS. Indeed, PGC1α overexpression or down-regulation prevents or exacerbates mtDNA loss and apoptosis. Overall the data highlight an anti-apoptotic role of PGC1α-mediated mitochondrial biogenesis in neuroblatoma cells and suggest PGC1α as a potential target for enhancing the effectiveness of therapy in aggressive neuroblastoma with high drug-resistance.