A catalyst-free method was developed for the ring opening of azlactones (also known as oxazolones) in water microdroplets. Azlactone was dissolved in a water : acetonitrile (1 : 1) mixture, and the solution is sprayed by using nitrogen gas at a pressure of 120 psi to generate microdroplets. This method promoted selective cleavage of the lactone bond to afford the corresponding N-benzoyl derivatives in up to 94% isolated yield with no epimerization. Our method produces the ring-opening products in milliseconds (up to 94 μmol for 33.3 minutes), and may have utility for high-throughput synthesis applications.