Materials functionalization through multicomponent reactions (MCRs) has recently attracted great attention due to the generation of outstanding features in materials. Herein, an efficient novel heterogeneous catalytic system was designed and synthesized via the MCRs functionalization of the most abundant biopolymer in nature, cellulose. In this regard, cellulose was oxidized using periodate as an oxidant agent, and then the resulted carbonyl functional groups participated in the three-component Betti reaction. The ICP-OES analysis was revealed that the functionalization of cellulose via this three-component reaction effectively improved the complexing ability of functionalized cellulose with Cu(II). The synthesized biocatalyst was characterized by FT-IR, 1H NMR, XRD, SEM, EDS, ICP, and TGA techniques. The efficiency of the designed biocatalyst was investigated in the C[sbnd]H functionalization reaction of N-acylhydrazones to synthesize 1,3,4-oxadiazoles. This biocatalyst's outstanding advantages are high yields, non‐hazardous catalyst, mild reaction conditions, operational simplicity, and reusability. © 2021