Highlights•Proanthocyanidins (PC) possessed anti-EV71 activitiesin vitrowith low toxicity.•PC may be able to block the binding and entry processes of EV71 in RD cells.•PC can bind to VP1 to interfere with the interaction between VP1 and SCARB2.•The MAPK signaling pathways may be involved in the anti-EV71 actions of PC.•PC can improve survival and attenuate clinical symptoms in EV71 infected mice.