Vascular endothelial growth factor (VEGF) is a secreted mitogen associated with angiogenesis and re-vascularization of spinal cord injury (SCI). VEGF has long been thought to be a potent neurotrophic factor for the survival of spinal cord neuron. However, the neuroprotective mechanism of VEGF is still unclear. The aim of this study was to investigate the effect of VEGF on spinal cord injury and its mechanisms. Young male Wistar rats were subjected to SCI and then VEGF165 were injected directly into the lesion epicenter 24 h post injury. We detected Basso, Beattie and Bresnahan (BBB) scores and numbers of motor neuron via Nissl staining. The expressions of autophagy related protein Beclin1 and LC3B were determined by Western blot and RT-PCR. We also detected the contents of inflammation factors interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α) and interleukin-10(IL-10) in LPS (Lipopolysaccharide) treated spinal neuron-glia co-culture by ELISA. We found that VEGF165 administration increased the BBB score and reduced the loss of motor neuron of rats induced by SCI. VEGF decreased the protein expressions of IL-1β, TNF-α and IL-10 and up-regulated the expressions of Beclin1 and LC3B of rats. In the in vitro study, VEGF165 decreased the levels of IL-1β, IL-10 and TNF-a in the medium of LPS treated spinal neuron-glia co-culture, which was partially blocked by 3-MA, the inhibitor of autophagy. In addition, VEGF165 up-regulate the expressions of Beclin1 and LC3B in co-culture cells. The results suggested that VEGF165 attenuated the spinal cord injury by inhibiting the inflammation and increasing the autophagy function. •VEGF inhibits inflammation through activating autophagy in vitro or in vivo.•VEGF attenuated neuron loss of SCI and improved neurobehavior function.•Neuronal protective effect of VEGF may have interaction with autophagy.