Palladium‐catalyzed activation of C–C bonds in organic molecules is a powerful tool for the synthesis of value‐added compounds. 5‐Hydroxymethylfurfural (HMF) derivatives are a promising class of biomass‐derived chemicals that have received considerable attention due to their potential applications in the synthesis of biologically active molecules and materials. However, the selective activation of unstrained C–C bonds is a challenging task, mainly due to their relatively high bond dissociation energies. Herein, we report a palladium‐catalyzed method for the efficient C–C bond activation of HMF derivatives, enabling their arylation with iodobenzenes. Mechanistic studies, including reaction‐profile analysis, competition experiments and head‐space IR‐spectroscopy suggest a decarboxylative mechanism.