Isocyanide multicomponent reactions play a prominent role in drug discovery. This chemistry has hardly been investigated for compatibility with DNA-encoded combinatorial synthesis. The Ugi, Ugi-azide, and Groebke-Blackburn-Bienaymé reactions are well-tolerated by DNA on the solid phase and show a broad scope. However, an oxadiazole-forming variant of the Ugi reaction caused DNA depurination, requiring a more stable hexathymidine DNA for encoded library synthesis. Cheminformatic analysis revealed that isocyanide multicomponent-reaction-based encoded libraries cover a diverse chemical space.