Objective: The purpose of the present study is to investigate whether angiopoietin-like 4 (ANGPTL4) can promote angiogenesis and neurogenesis following stroke, as well as to explore the potential underlying mechanisms. Methods: ANGPTL4 (40 μg/kg) or a vehicle was administered via tail vein beginning 5 min prior to electrocoagulation-induced stroke in male C57/B6 J mice. Infarct volume was measured via Nissl staining at day 3 post-stroke. Angiogenesis, neurogenesis and activation of microglia were evaluated by immunofluorescence co-labelling bromodeoxyuridine (BrdU) with von Willebrand factor (vWF), doublecortin (DCX), neuronal nuclei (NeuN) and Iba1 at day 7 post-stroke. The levels of p-AKT, T-AKT, VEGF, MPO, Fas and FasL in the ipsilesional brain were detected by Western blot analysis at day 1 post-stroke. Results: Compared with the Vehicle group, ANGPTL4 reduced infarct volume significantly at day 3 post-stroke. ANGPTL4 significantly increased the number of BrdU+, BrdU+/vWF+and BrdU+/DCX+ cells in the peri-infarct zone, subventricular zone and subgranular zone and inhibited BrdU+/Iba1+ cells in the peri-infarct zone at day 7 post-stroke. The level of p-AKT and the ratio of phospho-AKT to total-AKT in the ipsilesional brain were significantly elevated, the levels of MPO, Fas and FasL were significantly declined; however, there was no significant difference at day 1 post-stroke between the VEGF and total-AKT levels in both groups. Conclusions: ANGPTL4 enhances angiogenesis and neurogenesis post-stroke by upregulating the phosphorylation of AKT, reduces neuronal death and inhibits inflammatory response, which resultes from the inhibition of FasL/Fas expression and its downstream pathway. © 2021 Elsevier Inc.