Pyrroles are among the most privileged and influential small N-heterocycles at the core of many commercial drugs, biological composition, natural compounds, agrochemicals, and functional materials. Over the past several decades, various strategies have been developed for synthesizing pyrroles; however, most of these methods are step-by-step or multi-step strategies that suffer from waste material generation. Therefore, novel strategies with high efficiency to obtain polysubstituted pyrroles have high priority in synthetic organic chemistry. Isocyanide-based multicomponent reactions (I-MCRs) are one of the most interesting and efficient approaches and powerful toolbox for synthetic chemists to synthesize polysubstituted pyrroles. This strategy is a one-pot domino procedure, a simple and green approach that does not require an intermediate isolation or workup and is generally more efficient in terms of the use of materials. Also, it is a hot technique for synthesizing many biological compounds and commercial drugs. Today, many commercial drugs with pyrrole skeletal are being developed by researchers based on this strategy. The first review article using multicomponent reactions in the synthesis of pyrroles was reported by Menéndez et al. in 2010. After that, several review articles for pyrrole synthesis have been reported. However, it is fair to say that a review article under the title isocyanide-based multicomponent reactions for the synthesis of pyrroles in the literature does not exist. This review contains all research articles related to I-MCRs to synthesize polysubstituted pyrroles in the presence and absence of catalysts and their applications reported during the 2000–2021 period. This review article will be useful for organic chemists and pharmaceutical chemists to design new drugs and optimize the synthesis steps of many biological compounds and commercial drugs with pyrrole cores.