Natural products remain privileged starting points in drug discovery because of their structural complexity, stereochemical richness, and bioactive scaffolds. Semisynthesis enables the transformation of natural products or naturally occurring precursors into structurally modified analogs, helping overcome limitations in supply, physicochemical properties, toxicity, or pharmacokinetic behavior. In this context, isocyanide-based multicomponent reactions (I-MCRs) provide rapid, modular, and operationally simple synthetic tools for the diversification of natural product-derived substrates. This review summarizes the application of I-MCRs in natural product semisynthesis, including Ugi four-component reactions (U-4CR), Passerini three-component reactions (P-3CRs), Groebke–Blackburn–Bienaymé three-component reactions (GBB-3CRs), Ugi–azide four-component reactions (UA-4CRs), and other related I-MCRs. The collected literature indicates that U-4CR is the most-explored MCR, whereas P-3CRs, GBB-3CRs, and, particularly, the UA-4CRs remain underexplored. A chemoinformatic characterization of 162 semisynthetic I-MCR products revealed that these compounds occupy a chemical space comparable to that of FDA-approved natural product-derived drugs, while retaining natural product-like complexity and three-dimensionality. In addition, molecular docking against CXCR3 was performed as a hypothesis-generating approach to prioritize candidates for further biological evaluation. These findings highlight I-MCRs as promising synthetic tools for expanding natural product-related chemical space and generating structurally novel semisynthetic analogs.