To develop a novel celecoxib (CXB)-loaded drug delivery system, numerous nanosuspensions were prepared with various polymers and surfactants using a wet media milling process, and their particle sizes were subsequently determined. A 24 full factorial design was used to identify the most appropriate preparation conditions. Pharmacokinetics of the selected nanosuspension were performed in rats and compared with those of a drug powder and a commercial CXB-loaded product. Among the carriers investigated, copovidone and sodium lauryl sulphate gave the smallest particle size of the drug in the nanosuspension. In particular, the nanosuspension prepared with 5% CXB, 4% copovidone, and 0.1% sodium lauryl sulphate, under the appropriate conditions, showed a particle size of approximately 190 nm, which was physically stable for at least 8 weeks. This nanosuspension provided a significantly higher plasma concentration and AUC in rats as compared with the drug powder and the commercial product. Thus, this novel CXB-loaded nanosuspension is a promising candidate with excellent stability and enhanced oral bioavailability.