As a new type of transmission, the single-roller enveloping hourglass worm gear (SEHWG) is widely used in precision mechanical transmission systems. Time-varying mesh stiffness (TVMS) is one of the most important excitations, which has great influences on the dynamic characteristics of SEHWG systems. In this paper, a model for calculating the TVMS of the SEHWG is proposed, in which bending stiffness, shear stiffness, radial compression stiffness, and foundation stiffness are considered in the worm stiffness calculation. And bending stiffness, shear stiffness, and foundation stiffness are considered in the worm wheel stiffness calculation. The process of calculating the periodical TVMS of the SEHWG is also presented. Then, the TVMS of the SEHWG by the proposed method is compared with that of the finite element method for the model validation. Finally, the influences of the roller radii on TVMS are analyzed. The results show that the mesh stiffness of the TVMS has a tendency to rise first and then fall with the increasing roller radii.