Covalent organic frameworks (COFs) are porous and crystalline materials which are assembled from dynamic covalent bonds with two- or three-dimensional (2D or 3D) features. Unlike other polymers, COFs have significant and unique characteristics, including crystallinity, synthetic control, and structurally pre-designable aspects, among others. These notable intrinsic features render them an ideal platform energy conversion and storage, biomedical science, catalysis, sensing, separation, and adsorption applications. Solvothermal, sonochemical, ionothermal, microwave (MW), mechanochemical (MC) and multicomponent reaction (MCR) approaches are synthetic protocols that have been deployed for the construction of these fascinating materials. Herein, the most promising and relevant processing strategies are discussed for the formation of COFs via MCRs, highlighting the most important recent advances and encompassing the properties, characterization techniques, and production methods. A³-coupling, Povarov, Strecker, Groebke–Blackburn–Bienaymé, Debus–Radziszewski, and Doebner reactions are the MCRs that have been reported and summarized for the assembly of COFs. Furthermore, the successful usage of COFs to catalyze MCRs ranging from asymmetric synthesis to simple organic reactions is highlighted and discussed.