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A regioselective synthesis of isoxazoles with propargyl alcohols, N‐iodosuccinimide (NIS), and N‐tert‐butyl hydroxylamine hydrochloride (t‐BuNHOH•HCl) as the reaction substrates is reported. Reaction scope investigations indicated that primary and secondary propargyl alcohols underwent this transformation smoothly to afford 5‐, 3‐, and 3,5‐substituted isoxazoles in moderate to good yields. The reaction most likely involves an electrophilic‐intercepted Meyer‐Schuster rearrangement of the propargyl alcohol, followed by intermolecular cyclocondensation of N‐tert‐butyl hydroxylamine and in‐situ‐formed α‐iodo enones/enals. This one‐pot method is regioselective and easy to perform, making it a valuable method for the construction of isoxazoles. Finally, its application was explored through the synthesis of valdecoxib. A one‐pot and regioselective synthesis of isoxazoles involving propargyl alcohols, NIS, and t‐BuNHOH was investigated. In this process, α‐iodo enones/enals formed in situare the key intermediates and catalyst Bi(OTf)3has multiple functions. This method involves mild conditions, easy operation and scale‐up, broad substrate range, good functional‐group compatibility, and good regioselectivity. Notably, valdecoxib was prepared according to this method.