Membrane filtration is a key technology in dairy processing for the separation of dairy liquids to clarify, concentrate, and fractionate a variety of dairy products. Ultrafiltration (UF) is widely applied for whey separation, protein concentration and standardization, and lactose-free milk production, though its performance can be hindered by membrane fouling. As an automated cleaning process commonly used in the food and beverage industries, cleaning in place (CIP) uses large amounts of water, chemicals, and energy, resulting in significant environmental impacts. This study introduced micron-scale air-filled bubbles (microbubbles; MBs) with mean diameters smaller than 5 μm into cleaning liquids to clean a pilot-scale UF system. During the UF of model milk for concentration, cake formation was identified as the dominant membrane fouling mechanism. The MB-assisted CIP process was conducted at two bubble number densities (2021 and 10,569 bubbles per mL of cleaning liquid) and two flow rates (130 and 190 L/min). For all the cleaning conditions tested, MB addition largely increased the membrane flux recovery by 31–72%; however, the effects of bubble density and flow rate were insignificant. Alkaline wash was found to be the main step in removing proteinaceous foulant from the UF membrane, though MBs did not show a significant effect on the removal due to the operational uncertainty of the pilot-scale system. The environmental benefits of MB incorporation were quantified by a comparative life cycle assessment and the results indicated that MB-assisted CIP had up to 37% lower environmental impact than control CIP. This is the first study incorporating MBs into a full CIP cycle at the pilot scale and proving their effectiveness in enhancing membrane cleaning. This novel CIP process can help reduce water and energy use in dairy processing and improve the environmental sustainability of the dairy industry.