MgSO is widely used in the prevention of preterm neurological disabilities but its modes of action remain poorly established. We used a co-hybridization approach using the transcriptome in 5-day old mice treated with a single dose of MgSO (600 mg/kg), and/or exposed to hypoxia-ischemia (HI). The transcription of hundreds of genes was altered in all the groups. MgSO mainly produced repressions culminating 6 h after injection. Bio-statistical analysis revealed the repression of synaptogenesis and axonal development. The putative targets of MgSO were Mnk1 and Frm1. A behavioral study of adults did not detect lasting effects of neonatal MgSO and precluded NMDA-receptor-mediated side effects. The effects of MgSO plus HI exceeded the sum of the effects of separate treatments. MgSO prior to HI reduced inflammation and the innate immune response probably as a result of cytokine inhibition (Ccl2, Ifng, interleukins). Conversely, MgSO had little effect on HI-induced transcription by RNA-polymerase II. De novo MgSO-HI affected mitochondrial function through the repression of genes of oxidative phosphorylation and many NAD-dehydrogenases. It also likely reduced protein translation by the repression of many ribosomal proteins, essentially located in synapses. All these effects appeared under the putative regulatory MgSO induction of the mTORC2 coding gene. Lasting effects through and could account for this epigenetic footprint.