The traditional two-column reactive distillation (RD) process is used for the production of butyric anhydride, which is synthesized with butyric acid and acetic anhydride via a reversible reaction. In this work, a novel process with a single RD column (SRDC) is designed for the production of butyric anhydride, where the second distillation column for separating excess reactant is removed based on the boiling point profile of the reaction system. Two applications of the proposed SRDC process, namely SRDC with excess butyric acid or acetic anhydride circulating internally, are economically optimized, and the results show that both SRDC processes have a lower total annual cost (TAC) than the traditional two-column process. Furthermore, from the perspective of TAC, the application with an excess feed of butyric acid is better than the application with excess acetic anhydride. The developed technique may also be applied to retrofit other traditional two-column RD processes, where the overhead and bottom products are the lightest and heaviest components of the reaction system, respectively, and no azeotrope is involved in the RD column.