Conventional approaches to the synthesis of molecular knots and links mostly rely on metal templation. We present here an alternative strategy that uses the hydrophobic effect to drive the formation of complex interlocked structures in water. We designed an aqueous dynamic combinatorial system that can generate knots and links. In this system, the self-assembly of a topologically complex macrocycle is thermodynamically favored only if an optimum packing of all its components minimizes the hydrophobic surface area in contact with water. Therefore, the size, geometry, and rigidity of the initial building blocks can be exploited to control the formation of a specific topology. We illustrate the validity of this concept with the syntheses of a Hopf link, a Solomon link, and a trefoil knot. This latter molecule, whose self-assembly is templated by halides, binds iodide with high affinity in water. Overall, this work brings a fresh perspective on the synthesis of topologically complex molecules: Solvophobic effects can be intentionally harnessed to direct the efficient and selective self-assembly of knots and links.