Previous studies have found that Danhong injection (DHI), an extensively used herbal extract preparation in China, might be a powerful vasodilator. The aims of this study were to determine the vascular activity of DHI and its effects on arteries of different sizes. The results showed that DHI significantly inhibited rat-hindquarters and rabbit-ear vasoconstriction elicited by norepinephrine (NE) perfusion and markedly relaxed KCl-contracted and NE-contracted rat abdominal aortic and mesenteric artery rings. The endothelium made only a minor contribution to the vasorelaxant effect of DHI on artery segments. The vasorelaxant effect of DHI varied with the artery size, with larger arteries exhibiting a more sensitive and potent vasodilator response. DHI relaxed NE-induced vasoconstriction probably through inhibition of the intracellular Ca2+ release through the inositol triphosphate receptor system in the abdominal aorta and mesenteric artery, along with blockage of extracellular Ca2+ influx through the receptor-linked Ca2+ channels in the mesenteric artery. In addition, DHI completely relaxed KCl-induced contraction in both of the arteries, suggesting that inhibition of Ca2+ influx through voltage-gated Ca2+ channels is involved in the vasorelaxant effect of DHI. This elucidation of the vascular effects of DHI and the underlying mechanisms could lead to improved clinical applications.