Andean blackberry is a highly perishable fruit rich in anthocyanins and ellagitannins, and its short postharvest life significantly affects smallholder growers’ economies. Although crossflow microfiltration is a promising non-thermal stabilization technology for blackberry juice, its industrial application is limited by permeate flux decline during long-term operation, while most previous studies have focused on short processing times. This study evaluated the effect of high-shear homogenization prior to enzymatic depectination on flux decline, product quality, and techno-economic feasibility during CFM. Juice processed by conventional grinding followed by high-shear homogenization and enzymatic treatment was subjected to CFM at feed volumes up to 400 L and volumetric reduction factors close to 30. Homogenization significantly reduced particle size and suspended insoluble solids, resulting in higher permeate flux, improved flux stability, and greater productivity. Flux decline analysis showed that high-shear homogenization extended the stable filtration regime and delayed severe fouling, sustaining higher average permeate fluxes during long-term operation. Product quality was preserved, ensuring microbial reduction while improving anthocyanin and ellagitannin recovery and enhancing blackberry aroma. In addition, HS3+E reduced energy consumption and beverage production cost while achieving a positive NPV and a 21% IRR. Overall, homogenization improved the industrial feasibility of long-term CFM processing of Andean blackberry juice.