Renewable bio-based adhesives help to address environmental pollution, non-renewable petrochemical resources usage and formaldehyde emissions in the wood-based panel industry. Soybean protein isolate (SPI) adhesive has great potential to replace formaldehyde-based adhesive, but it has problems such as poor antibacterial effect, poor water resistance, weak adhesive strength, and high brittleness. This work has extracted the active substance (SE), which contains flavonoids, and derived cellulose nanocrystals (CNC) from the roots of Stellera chamaejasme. The SPI lateral chains amino groups react with flavonoids in SE under alkaline conditions; the incorporation of flavonoids rather than widely used tannin with SPI results in the desired crosslinking efficiency and satisfied interfacial adhesion, while the crosslinking agent oligo(ethylene glycol) hydrazine derivative (BHTA) with multiple epoxy groups undergoes a ring-opening reaction to form a waterproof multiple cross-linked network. Mineralized CNC can improve the adhesive's load transfer and energy dissipation capabilities, and introduce metal coordination to enhance the toughness and bonding strength of SPI adhesives. These synergistic effects significantly improve the water resistance and bonding strength. Consequently, the dry and wet bonding strength are 4.19 MPa and 1.17 MPa, respectively. Furthermore, this novel adhesive performs excellent anti-decay and anti-mold effects. Therefore, this study could guide the future development of bio-adhesive materials.