An efficient and highly regioselective one‐pot three‐component synthesis of previously inaccessible and synthetically demanding 3‐(cycloalkyl/alkyl/arylamino)‐5‐aryl/alkylisoxazoles has been achieved by the cyclocondensation of β‐oxo dithioesters, amines and hydroxylamine in ethanol at reflux. This transformation proceeds via an in situ generated β‐oxothioamide by the reaction of the β‐oxo dithioester and amine, which undergoes nucleophilic attack by hydroxylamine followed by intramolecular cyclization with the oxo functionality and subsequent dehydration to give 5‐substituted 3‐aminoisoxazoles as a single regioisomer in good yields. Furthermore, the mechanism of the reaction has been established experimentally and shown to be in agreement with the hard and soft (Lewis) acid and base (HSAB) theory.