Purpose A pulsatile drug delivery system containing dexketoprofen trometamol was designed by combining immediate release and colon-targeted mini tablets into a capsule. Methods Both immediate release and colon-targeted mini tablets were prepared by wet granulation. Furthermore, colon-targeted mini tablets were coated with Eudragit L 100, Eudragit S 100, Eudragit RS 30D, and ethylcellulose (Surelease (R)) using Wurster and pan coating methods. Results The optimum drug release of the system developed in the study was found to be mini tablets coated with 30% Eudragit S 100 on a 20% Surelease (R) subcoating for the purpose of colon targeting. Conclusion In the finished product, the immediate release part released the drug within the first hour, and less than 5% release was observed from the colon-targeted tablets in a 0.1 N HCl in 2 h. Then, less than 20% release occurred in the colon-targeted tablets up to 6 h in pH 6.8 phosphate buffer solution. The cumulative release rate reached 100% for up to 12 h. To our knowledge, it was the first time dexketoprofen trometamol was designed by combining both immediate release and colon-targeted mini tablets in a one dosage form.