The potential of synthesizing new nano-composites from nanocrystalline cellulose (NCC) and fibrin for small-diameter replacement vascular graft (SDRVG) application was demonstrated. Periodate oxidation of NCC can augment reactive carbonyl groups on NCC and facilitate its cross-linking with fibrin. NCC-fibrin nanocomposites were synthesized, composed of homogeneously dispersed oxidized NCC (ONCC) in a fibrin matrix, with fibrin providing elasticity and ONCC providing strength. The maximum strength and elongation of the nanocomposites were determined by Atomic Force Microscopy (AFM) and compared with a native blood vessel. The manipulation of degree of oxidation of NCC and the NCC-to-fibrin ratio resulted in the variation of strength and elongation of the nanocomposites, indicating that the nanocomposites can be tailored to conform to the diverse mechanical properties of native blood vessels. A mechanistic understanding of the molecular interactions of ONCC and fibrin was illustrated. This study established fundamental information to utilizing NCC for SDRVG applications.