This review has been centralized on applications of phthalic anhydride (PA) as a valuable and significant heterocyclic substrate in two- and multicomponent organic reactions. The article has been subdivided into the following parts: (i) PA introduction by focusing on its characterization, synthesizing procedure, and multiple-aspect applications. In addition, the previous review articles based on PA have also been indicated; (ii) the applications of PA as a substrate have been subdivided into parts with a glance on the reaction components numbers; (iii) the applications of PA in esterification reactions; and (iv) some examples of PA in multistep synthesis. The review covers the corresponding literature up to the end of 2022. According to the abovementioned classifications, PA is a potent substrate to design a wide range of heterocyclic compounds that possess various kinds of properties and applications in chemistry, industry, and pharmaceuticals.