Long non-coding RNA H19 (H19) is one of the earliest discovered long non-coding RNAs. H19 induced the onset of ischemic stroke through regulating neuronal autophagy and microglial polarization. And we aimed to study whether H19 participated the neurogenesis process after ischemic stroke. Circulating H19 levels in ischemic stroke patients and the mRNA levels of p53 target genes were tested by real-time polymerase chain reaction. H19 small interference RNA and pifithrin-α were used to inhibit H19 and p53 expression in the mice suffered middle cerebral artery occlusion, respectively. The expression of neurogenesis related proteins was assessed by Immunofluorescence and Western blot. Circulating H19 levels were positively associated with the National Institute of Health Stroke Scale Scores of the patients in 7d, 30d and 90d after stroke attack., H19 small interference RNA significantly decreased the volume of brain tissue loss at 14d after middle cerebral artery occlusion and reperfusion in mice and promoted the neurological deficit recovery of the mice. It was confirmed by immunofluorescence that H19 knockdown could decrease the fluorescence intensity of neurogenesis related proteins. While inhibiting p53 on the basis of H19 knockdown reversed the pro-neurogenesis effect of H19 inhibition. Furthermore, H19 decreased the transcriptional activity of p53 and the expression of Notch1, and p53 inhibition abolished these effects of H19. Our findings demonstrate that H19 prevents the process of neurogenesis after ischemic stroke through p53/Notch1 pathway and strengthen the novel role of H19-based therapy for ischemic stroke. Copyright ? 2019. Published by Elsevier Inc.