High pressures can be employed in shear-enhanced nanofiltration (NF) process in order to obtain large permeate flux, and under this extreme hydraulic condition, membrane fouling behavior may be different and need to be investigated. In this study, a rotating disk laboratory module capable of very high shear rates and pressure was used to treat model dairy wastewater with a NF270 membrane. The presence of lipids had a negligible effect on flux profile and permeate quality, although it slightly increased adsorption fouling. Higher shear rates decreased concentration polarization and produced higher permeate fluxes with lower permeability loss. After the flux remained stable for several hours, adsorption fouling and subsequent cake layer formation occurred. The surface adsorption of small foulants such as lactose and calcium ions caused a slow flux decline, and in the absence of chemical cleaning, it induced cake fouling and severe flux decline. Inorganic ions such as calcium and phosphate engaged with milk proteins in micelles or aggregates, and thus inorganic scaling was negligible and alkaline cleaning could remove most surface fouling. We concluded that, with suitable chemical cleaning, a high and stable flux could be obtained for a long time in dairy wastewater treatment by NF under shear-enhanced extreme hydraulic conditions.