Macroscopic mechanical force has attracted much attention as an existing yet novel energy source for modification of molecular interactions and molecular reactivity. Although various molecular level phenomena have been controlled by using macroscopic mechanical forces, control of host–guest inclusion has not been a research target. Here we report a novel controlled release system triggered by a mechanical stimulus. Release of ondansetron (ODN), an anti-emetic drug, from a designer hydrogel composed of a β-cyclodextrin (CyD) derivative and alginate (AL) can be controlled by mild mechanical compressions that mimic operation by a patient's hand. ODN is released in response to mechanical compressions by changing the inclusion ability of CyD moieties, which may be conformationally distorted, and/or suppressed stabilization of the inclusion complex when an external stress is applied. It is revealed that the release can be induced even by the slight conformational restriction for β-CyD due to the mechanical stimulus. This controlled release technology provides a novel dosing strategy enabling on-demand administration of medicines through a mechanical stimulus generated intentionally by the patient.