One major challenge in utilization of ultrafiltration (UF) membrane for wastewater treatment is its inevitable tendency of biofouling (from biomolecules to microorganisms). To overcome this challenge, nanostructured cellulose membranes with hydrophilic surface and high porosity (∼80% without pressurization) was demonstrated in this study. The cellulose membrane consisted of a lyocell microfiber scaffold infused with cellulose nanofibers (CNF), crosslinked with polyamideamine-epichlorohydrin (PAE). The demonstrated membranes showed good mechanical strength (wet stress: 3.5–8.0 MPa), pH resistance (pH 2.5–9.0) and stability in hot water (60 °C). The optimized cellulose membrane exhibited high permeation flux (127.6 ± 21.8 L m−2 h−1 bar−1), excellent separation efficiency (>99.9%), good flux recovery ratio (>95%) and self-healing ability for wastewater filtration, compared with commercial polymeric membranes (e.g., polyvinylidene difluoride (PVDF) and polyether sulfone (PES)). The resistance-in-series and three combined cake-filtration models were applied to investigate the fouling behavior of the cellulose and PVDF/PES UF membranes. While all membranes suffered cake layer precipitation and pore blocking issues, the cellulose membranes exhibited near total recyclability upon washing due to the hydrophilic and negatively charged CNF membrane surface. This study illustrated the promising potential of using cellulose membranes for high-efficient wastewater treatment and its superior antifouling performance compared to existing commercial membranes.