Hypoxia-inducible factor 1α (HIF-1α) promotes cell survival after hypoxia-ischemia by regulating its target genes. Desferrioxamine (DFO) has been found to up-regulate HIF-1α expression in ischemia brain injury. However, the signaling pathway to mediate this regulation remains unclear in neonatal hypoxia-ischemia brain damage (HIBD). Since phosphoinositide 3-kinase (PI3K/Akt) pathway and extracellular signal-related protein kinase pathway (Erk1/2 MAPK) have proven to be involved in the regulation of HIF-1α in neonatal rat brain after hypoxia-ischemia (HI), we hypothesized that DFO might regulate HIF-1α by activating PI3K/Akt and Erk1/2 MAPK pathways in developing rat brain after HI. To test this hypothesis, we subjected postnatal day 10 rats to DFO intraperitoneal injection 30 min before HI. Rat brains were collected to detect the expression of HIF-1α and its target gene VEGF, as well as PI3K/Akt and Erk1/2 MAPK using Western blot analysis. We found that the expression of HIF-1α, VEGF, and p-Erk1/2 was significantly up regulated and peaked at 4 h after HI in DFO treated group, with higher level and earlier peak time than control group. However, the expression of p-Akt was unchanged in DFO treated group compared with control group. Our findings suggest that DFO might up-regulate HIF-1α and its target gene VEGF through Erk1/2 MAPK pathway in the developing rat brain after HI.