Biofouling is a pervasive problem for any materials that are exposed to aquatic environments. Especially, it is a dire problem for the desalination membranes used to sustainably supply clean water, necessitating development of the methods to mitigate membrane biofouling. We present a topological modification approach to achieve ultralow fouling of water desalination membranes by realizing the sharkskin-mimetic (Sharklet) surface patterns and identify their unique antifouling mechanism based on computational fluid dynamics simulation. Our approach relies on a newly developed layered interfacial polymerization that can produce a conformal selective layer on patterned porous supports prepared by phase separation micromolding. The Sharklet-patterned membrane exhibited remarkably low biofouling compared to the conventional membranes with irregular roughness and topologically modulated membranes with simple patterns. Its superior biofouling resistance is attributed to the unique Sharklet geometry that can significantly inhibit biofilm growth. Furthermore, under dynamic flow conditions, the intricate Sharklet geometry induces a complex surface flow by symmetrically generating a secondary flow perpendicular to the primary flow, forming a periodic inflow and outflow along the pattern. The reinforced primary and secondary flows of the Sharklet pattern may further contribute to its excellent biofouling resistance.