Defect chemistries of metal-doped CeO2 catalysts have attracted extensive scientific interests in heterogeneous catalysis. Here, we report the structure–activity relationship of CeO2 catalysts doped by Pr. The Pr-doped CeO2 solid solution catalysts were prepared by a coprecipitation method and evaluated in Prins condensation–hydrolysis of isobutene with formalin to 3-methyl-1,3-butanediol. Raman and infrared (IR) spectroscopies were used to characterize the defect sites of the catalysts. Pr creates two kinds of defects in Pr-doped CeO2: oxygen vacancy and lattice distortion (Pr3+O8-type complex, which was confirmed by the Raman and XPS spectra), whose concentrations depend on the Pr doping amount. The relationship between defect properties (type and concentration) and their catalytic consequence is established. The catalytic performance significantly depends on the oxygen vacancy concentration in Pr-doped CeO2 catalysts. This study also shows that a Pr3+O8-type complex has little effect on the catalytic performance, indicating that the Pr3+O8-type complex is a spectator during the reaction. DFT calculations have indicated that the oxygen vacancy induced by the Pr dopant on a CeO2 surface promotes the adsorption of HCHO and inhibits the adsorption of isobutene, suggesting the condensation of HCHO and isobutene occurs via an Eley–Rideal (ER) mechanism.