Cellulose acetate (CA) is widely used in the preparation of ultrafiltration membranes due to its many excellent characteristics, especially chemical activity and biodegradability. To improve the inherent hydrophobic and antifouling properties of CA membrane, in this work, CA was successfully modified with dopamine (CA-2,3-DA) through selective oxidation and Schiff base reactions, which was confirmed by FTIR and
1
H NMR measurements. Then, CA-2,3-DA membrane with high water permeability and excellent antifouling property was prepared by the phase inversion method. Compared with the original CA membrane, the CA-2,3-DA membrane maintained a higher rejection ratio for BSA (92.5%) with a greatly increased pure water flux (167.3 L m
−2
h
−1
), which could overcome the trade-off between permeability and selectivity of the traditional CA membrane to a certain extent. According to static protein adsorption and three-cycle dynamic ultrafiltration experiments, the CA-2,3-DA membrane showed good antifouling performance and superior long-term performance stability, as supported by the experimental results, including flux recovery ratio, flux decline ratio, and filtration resistance. It is expected that this approach can greatly expand the high-value utilization of modified natural organic polysaccharides in separation engineering.