The development of a superior feed channel spacer is one among the problems that have to be resolved to effectively mitigate foulant accumulation in the membrane system and improve filtration performance. In view of this, a novel honeycomb-shaped spacer, whose hexagonal form is the most stable and economical structure observed in nature, is proposed. 3D printing enables us to manufacture the honeycomb-shape spacer. Then, the performance of such spacer is demonstrated by comparing its filtration results with those of a standard diamond-shaped spacer in nanofiltration. The proposed structure is observed to have higher fouling mitigation performance under various fouling conditions (i.e., low and high fouling potentials and different organic foulants). Optical coherence tomography demonstrates that the foulant layer formed by utilizing honeycomb-shaped spacers (119.0 μm) is significantly thinner than that resulting from the use of standard spacers (175.5 μm); thereby, the permeate flux of the honeycomb-shaped spacers was 16.0% greater than that of the standard spacers. Hydraulic cleaning tests reveal that honeycomb-shaped spacers have a higher potential for mitigating fouling resistances driven by the concentration polarization layer (Rcp) and cake layer (Rc), leading to higher permeate production than that generated by filtration using standard spacers. The use of computational fluid dynamics simulation affords better insights into the hydrodynamic effects of these spacers on the feed channel. It is observed that honeycomb-shaped spacers have superior performance that is attributable to the generation of high-magnitude turbulent kinetic energy in the areas enclosed by spacer filaments.