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Proteolysis‐targeting chimeras (PROTACs) have become a popular therapeutic strategy, and the development of multi‐functional PROTACs has added complexity to their synthetic process. Although click reactions have been widely applied to prepare highly functionalized biomolecules, most of them are limited to two‐component reactions, restricting the creation of more complex structures. Here, we developed a convenient multi‐component assembly strategy via strain‐promoted alkyne–nitrone cycloaddition (SPANC), which can be extended to a 3‐component reaction when combined with nitrone formation. Using the 2‐component assembly, we demonstrated the targeted protein degradation with both preassembled and in‐cell assembled PROTACs. This strategy was also applied to facilitate the screening of E3 ligases in PROTACs and the preparation of various biological probes. Moreover, the 3‐component assembly, via sequential nitrone formation and SPANC, enabled the synthesis of trifunctional 3‐component PROTACs. The N‐substituent, serving as an additional functional moiety, was designed as a photocage for sterically controlling PROTAC activity. The 3‐component assembly can be further modified to provide additional control or enhance the cell‐targeting ability of PROTACs. In short, our multi‐component SPANC assembly strategy offers a modular and versatile synthetic platform for creating multi‐functional PROTACs and biological probes. [ABSTRACT FROM AUTHOR]