The purpose of this study was to establish a rationale for the cleaning of microfilteration (MF) membranes fouled by milk. Milk was processed using a hydrophilic GVWP membrane. Fouling is the most important problem associated with the membrane-based milk sterilization process. This is mostly due to the deposition of bacteria, fats, proteins, and minerals on the membrane surfaces. In the first part of this work, the factors affecting the chemical cleaning efficiency were studied. This includes the effect of concentration, temperature, cleaning time, and cross-flow velocity. A wide range of cleaning agents including acids, bases, and surfactant was used. Flux recovery (FR) was employed for presenting the cleaning efficiency. In the second part of this study, FR was optimized using response-surface methodology with a face-centered central composite design (CCF). This was employed to create the mathematical model and minimize the number of experiments. © Taylor & Francis Group, LLC.