A rapid method has been developed for the synthesis of 3‐arylphthalides from readily available starting materials. We describe herein a direct approach based on a simple Friedel‐Crafts condensation between an aromatic ester and an aldehyde promoted by a mixture of phosphorus pentoxide and methanesulfonic acid (Eaton’s reagent) under metal and solvent‐free conditions. Due to their similarity to cytosporone E (a natural antibacterial phthalide), some of the synthesized compounds were tested as antibacterial agents against methicillin‐resistant strain of Staphylococcus aureus.