Guest molecular diffusion in porous crystalline materials is pivotal in their functionality, stability, and reactivity. Understanding the diffusion behavior of guest molecules in clathrate frameworks has been hindered, however, by the lack of experimental data and theoretical investigations over long time scales. We report here extremely slow diffusion of argon atoms in hydroquinone clathrate, an exemplary host–guest material. The diffusion coefficient of argon in one-dimensional cage channels of hydroquinone clathrate is estimated as 4.9 × 10–19 m2 s–1 at 298 K with an activation energy of 79.1 kJ mol–1. This value is 4 orders of magnitude slower than the diffusivities of all clathrate materials reported to date. Coupled with the umbrella sampling method, molecular dynamics simulations reveal that no spontaneous hopping events of atoms across the neighboring cages occur during one microsecond as the hydrogen-bonded hexagonal entrance of the cages sets a high energy barrier for diffusion. Our results shed light on the long-term stability of clathrate compounds as well as on tailoring guest–host materials for gas storage.