The acidities (pK(a) values) of proline amide derivatives are of great importance for understanding the catalytic activity of proline-based organocatalysts. The development of new catalysts could also benefit from the systematic study of the pK(a) values of these compounds. However, only a few pK(a) values of the proline-based organocatalysts are currently available due to the difficulty in experimentally measurements. In this work, we set out to study the pK(a) values of various proline amide derivatives with theoretical calculations. Different theoretical methods were evaluated and the combined method, B3PW91/6-311++G(3df,2p)//B3LYP/6-31+G(d)//HF//CPCM/UA0, was found to be the best one in reproducing the pK(a) values of structurally unrelated amides and amide derivatives in DMSO. The MAD and RMSE of the newly developed theoretical model equal to 0.98 and 1.3 pK units, respectively. The method also enabled the systematically study on various structural effects on pK(a) values of proline amide derivatives, such as the ZE-isomerization, remote substitution, and alpha-substitution effects, for the first time. The pK(a) values of a series of chiral amides were also studied in this work. Finally, we applied the theoretical method to predict a large number of proline-based organocatalysts and established an extensive acidity scale of the compounds.