To overcome the limitations of the conventional particle size reduction technologies, a novel combinative particle size reduction method for the effective production of homogeneous nanosuspensions was investigated. Ursodeoxycholic acid, a poorly soluble drug representative, was tried to prepare nanosuspension by homogenization technology and high-pressure precipitation tandem homogenization technology. It was shown that the combinative approach could significantly improve the particle size reduction effectiveness over conventional homogenization approach. The Box-Behnken design analysis for process optimization revealed that the acceptable UDCA-NS was obtained wherein the optimal values of A, B, C and D were 10%, 500 bar, 0.125 and 600 bar, respectively. SEM results demonstrated that no significant aggregation or crystals growth could be observed in the freeze-dried UDCA nanocrystals. The DSC and XRD results showed that UDCA remained in a crystalline state. Dissolution velocities of the freeze-dried UDCA-NS powder were distinctly superior compared to those of the crude powder and physical mixture. The high-pressure precipitation tandem homogenization technology can be a good choice for nanosuspension preparation of poorly soluble UDCA, due to high efficiency of particle size reduction.