Precise control over guest uptake and release in molecular cages is critical for applications in catalysis and chemical separations. Here we report a strategy for regulating the rate of internally-bound anion exchange within an FeII4L6 metal-organic tetrahedron through external coordination of tripodal tris(alkylammonium) cations. The cage features three flexible 18-crown-6 receptors at each of its FeII vertices, facilitating strong tritopic interactions with tris(ammonium) cations to ‘cap’ the vertices of the tetrahedron. This vertex-capping mechanism restricts the flexibility of the cage framework, which reduces the rate of anion exchange within its central cavity 20-fold when tris(ammonium) cations are bound externally. Thus, we demonstrate the use of an externally-bound multivalent effector for allosteric control over internal guest binding in a molecular cage.