Beneficial effects could be achieved by various agents such as nitroglycerin, botulinum toxin A (BoTA), and clopidogrel to improve skin flap ischaemia and venous congestion injuries. Eighty rats were subjected to either arterial ischaemia or venous congestion and applied to a bipedicled U-shaped superficial inferior epigastric artery (SIEA) flap with the administration of nitroglycerin, BoTA, or clopidogrel treatments. After 7 days, all rats were sacrificed for flap evaluation. Necrotic area percentage was significantly minimized in flaps treated with clopidogrel (24.49%) versus the ischemic flaps (34.78%); while nitroglycerin (19.22%) versus flaps with venous congestion (43.26%). With ischemia, light and electron microscopic assessments revealed that nitroglycerin produced degeneration of keratinocytes and disorganization of collagen fibers. At the same time, with clopidogrel administration, there was an improvement in the integrity of these structures. With venous congestion, nitroglycerin and BoTA treatments mitigated the epidermal and dermal injury; and clopidogrel caused coagulative necrosis. There was a significant increase in tissue gene expression and serum levels of vascular endothelial growth factor (VEGF) in ischemic flaps with BoTA and clopidogrel, nitroglycerin, and BoTA clopidogrel in flaps with venous congestion. With the 3 treatment agents, gene expression levels of tumor necrosis factor-α (TNF-α) were up-regulated in the flaps with ischemia and venous congestion. With all treatment modalities, its serum levels were significantly increased in flaps with venous congestion and significantly decreased in ischemic flaps. Our analyses suggest that the best treatment option for ischemic flaps is clopidogrel, while for flaps with venous congestion are nitroglycerin and BoTA.