The invention relates to an alprostadil nanoparticle preparation and a preparation method thereof. The preparation is essentially used for transdermal administration and used for treating diseases such as diabetic ulcer, ischemia of extremity end, burn and the like, and belongs to the technical field of medicine. The preparation consists of the raw materials according to the following weight ratio: alprostadil: lipid component: emulsifier: excipient matrix: water is 0.01-0.1:0.5-10:0.5-5:550-950:5-95. The alprostadil nanoparticle preparation has the advantages of overcoming the chemical and physiological instability of the alprostadil, strengthening in vitro stability, reducing degradation of the alprostadil caused by inactivation effect of in vivo pulmonary circulation, enhancing concentration of the preparation on the local affected parts, being more easy to aggregate at the affected part, sustained release and long effect, and reducing irritation of the medicine.