Aim To investigate the effect of vitexin on hypoxia/reoxygenation (H/R)-induced myocardial cell injury and its regulatory relationship with FGD5-AS1. Methods Rat cardiomyocytes H9c2 were divided into control group, H/R group, H/R+vitexin L, M,Hü group, H/R+pcDNA group, H/R+pcDNA-FGD5-AS1 group, H/R+vitexin+si-NC group and H/R+vitexin+si-FGD5-AS1 group. Cell apoptosis was detected by flow cytometry, Caspase-3 and cleaved Caspase-3 protein expressions were detected by Western blot, and the activity of SOD and the content of MDA in cells were detected by kits. The expression of FGD5-AS1 was detected by RT-PCR. Results Compared with H/R group, the apoptosis rate of H/R+vitexin L, M,Hü groups was decreased by 13%, 25% and 48%, respectively; Caspase-3 protein expression was decreased by 21%, 38% and 56%, respectively; Cleaved Caspase-3 protein expression was decreased by 17%, 40% and 65%, respectively; And MDA content was decreased by 15%, 36% and 52%(P＜0.05); But the activity of SOD was increased by 0.8,2.73 and 3.86 times, and the expression of FGD5-AS1 was increased by 0.4,1.84 and 3.00 times (P＜0.05). Compared with H/R+pcDNA group, the apoptosis rate, Caspase-3 and cleaved Caspase-3 protein expressions and MDA content were decreased in H/R+pcDNA-FGD5-AS1 group by 60%, 70%, 74%, and 60%, respectively (P＜0.05), but the activity of SOD was increased by 4.04 times (P＜0.05). Compared with the H/R+vitexin+si-NC group, the apoptosis rate of H9c2 cells, the expressions of Caspase-3 and cleaved Caspase-3 protein and the content of MDA were increased in the H/R+vitexin+si-FGD5-AS1 group by 0.2,1.1,1.8,0.93 times (P＜0.05), but the activity of SOD was decreased by 67%(P＜0.05). Conclusion Vitexin could inhibit H/R-induced apoptosis and oxidative stress of H9c2 cells, and its mechanism may be related to the up-regulation of FGD5-AS1 expression in cells.