Backgrounds Polydatin (PD, 3, 4’, 5-Trihydroxystibene-3-beta-monoglucoside) is a monocrystalline drug isolated from Polygonum Cuspidatum. It has obtain permission for phase II clinical trials from the Chinese Food and Drug Administration (Clinical Trials.gov identifier: 2006L00301), as well as from the American Food and Drug Administration (Clinical Trials.gov identifier: NCT 01780129). This study tests the hypothesis that polydatin attenuate vascular hyperpermeability after burn by inhibiting the activation of the intrinsic apoptotic pathway. Materials and Methods Scalp-induced edema model of rat ears was used to find out the effect of polydatin gel. Experimental rats which subjected to burn injury covering 30% of the total body surface area were used to explore its mechanism. PD, cyclosporine A (CsA), or resveratrol (Res) was administered to the animal model after burn injury. The rats were injected with fluorescein isothiocyanate albumin (50 mg/kg), and changes in the integrated optical intensity of the postcapillary venules were determined by intravital microscopy. The permeability of mesenteric venules was assessed. Expression of cytochrome C and Smac in cytosolic fraction, as well as expression of Bcl-2 and Bax in mitochondrial fraction, were analyzed by Western Blotting. Caspase-3 activity was detected with Caspase-3/CPP32 Fluorometric Assay Kit. Results The permeability coefficient of the burn skin venules in the burn+NS group was higher than that in the sham burn group (P < 0.01). Observed by the video micro scaler, pinnae swelling was obvious in rats immediately after burn, and no blood circulation could be detected. The wound edema reduced and the blood flow began recovery after 6 hours after PD administrating. Treated with CsA, Res, or PD resulted in a reduction in the FITC-BSA extravasation. The results of Western Blotting indicated that the levels of cytochrome c and Smac in the cytosol of the mesenteric vasculature in the sham burn group were significantly lower than those in the burn+NS group at 6 h after burn. Treatment with CsA, Res, or PD reduced the cytosolic release of cytochrome c and Smac. This reduction was more significant in the burn+Res and burn+PD groups (both, P< 0.01) than in the burn+NS group. Burn injury resulted in the upregulation of Bax proteins and downregulation of Bcl-2 in the rat mesenteric microvasculature. Treatment with CsA, Res, or PD could attenuate these changes to some extent. The level of caspase-3 activity in the mesenteric microvasculature showed that the level was increase in the burn+NS group, the burn+Res and burn+PD groups showed significantly lower levels (both P< 0.01) than the burn+NS group after treatment. Conclusion PD markedly attenuated burn-induced local and systemic hyperpermeability which caused by the activation of endogenous apoptotic signaling pathway.