The sustained release of antimicrobial therapeutics for wound dressing has become an attractive design strategy for prolonging the timespan of wound dressings and for reducing the risk of chronic wound infection. Recently, cellulose-based membrane has become a preferred option of wound dressings for the treatment of burn wounds and skin ulcers. In this work, novel cellulose membrane incorporated with mesoporous silica particles (SBA-15) was developed as an antimicrobial wound dressing with desirable sustained release functionality for targeting persistent bacterial pathogens. Attributed to a coated layer of calcium carbonate (CaCO3), SBA-15 particles were free from corrosion in alkaline condition during the preparation of cellulose-based composite membranes. SEM, TEM and BET results showed that the morphology, specific surface area, pore size and pore volume of pristine SBA-15 were preserved after the incorporation of CaCO3-coated SBA-15 into the cellulose matrix, while the mesoporous structure of SBA-15 was significantly disrupted without the use of CaCO3 coating. The resultant composite membranes containing 30 wt% SBA-15 (denoted as CM-Ca2-SBA(30%)) achieved 3.6 wt% of antimicrobial drug loading. Interestingly, CM-Ca2-SBA(30%) demonstrated the sustained release property of chloramphenicol for 270 h, driven by a two-stage drug release processes of SBA-15/cellulose. The water vapor permeability (WVTR) and swelling properties of composite membranes were shown to have complied with the primary requirements of wound dressing. Antibacterial assays revealed that strong antibacterial activities (144 h) of the composite membranes against Staphylococcus aureus and Eschericia coli were achieved. All results displayed that the strategy of coating silica with CaCO3 helps to obtain cellulose–silica composite membranes with desirable sustained release profiles and strong antibacterial activities. The antibacterial SBA-15/cellulose composite membranes show potential for the application of wound dressing.