The multicomponent Petasis borono–Mannich (PBM) reaction is a useful tool for the preparation of complex molecules in a single step from boronic acids, aldehydes/ketones, and amines. Here, we describe the use of glycerol in the PBM reaction of salicylaldehydes or 2-pyridinecarbaldehyde with several boronic acids and secondary amines. From these readily available starting materials, alkylaminophenols, 2-substituted pyridines, and 2H-chromenes were prepared in reasonable to good yields. Glycerol was compared with other solvents, and in some cases, it provided the reaction product in higher yield. Crude glycerol, as generated by the biodiesel industry, was evaluated and found to be a suitable solvent for the PBM reaction, successfully expanding the potential use of this industry by-product. Based on density functional theory (DFT) calculations and the obtained experimental results, the involvement of glycerol-derived boronic esters in the reaction mechanism is suggested to be competitive with the free boronic acid pathway. Similar Gibbs free energies for the aryl migration from the boronate species to the iminium were determined for both mechanisms.