Tangential flow filtration (TFF) perfusion using hollow‐fiber modules offers substantial advantages over other mammalian cell retention technologies. Recently, increased awareness of Starling flow has helped to enhance filtration performance to similar, or even higher levels compared to alternative technologies. Despite these improvements, scaling TFF perfusion remains challenging and often requires time‐consuming trial‐and‐error efforts. This manuscript presents a systematic, data‐driven four‐step workflow for designing and scaling TFF perfusion systems, integrating hydraulic considerations, bubble removal studies, and pump characterizations. While filter selection in TFF perfusion often receives significant attention, the design of the cell retention loop is commonly overlooked. However, this element plays a crucial role in system performance and can cause suboptimal pump operation, residence time issues, and bubble accumulation. The developed data‐driven workflow facilitates the optimization of designs for generic TFF perfusion systems utilizing hollow‐fiber modules, effectively bridging the gap between small‐scale and manufacturing‐scale implementations.