A chemo-electro-mechanical model is presented for analysis of the influence of the initial fixed charge density on performance of ionic-strength-sensitive hydrogel, termed the multi-effect-coupling ionic-strength-stimulus (MECis) model. It is composed of Nernst–Planck convection–diffusion equations which describe the chemical field, Poisson equation which provides the electrical potential associated with the fixed charge equation based on the Langmiur adsorption theory, and the mechanical equation which demonstrates the deformable behavior of the polymeric network of the ionic-strength-sensitive hydrogel. In the MECis model, the ionic strength of the bathing solution is considered as a key stimulus and incorporated into the Nernst–Planck equations and fixed charge formulation via activity coefficient and apparent dissociation constant, which influence the convection–diffusion characteristics and binding reaction. The initial fixed charge density is taken as an important chemical parameter for the indication of the amount of the ionizable monomer groups within the ionic-strength-sensitive hydrogel, since it reflects the swelling ability of the hydrogel. The initial fixed charge density also influences the binding ability of the mobile ions to the polymeric network that determines the driving force for the swelling, which is reflected by the fixed charge equation in the MECis model. The present simulation results are compared with the experiments for examination of the MECis model, and it is concluded that the MECis model can predict well the influence of the initial fixed charge density on the swelling behavior quantitatively and provide a good simulation platform for designing and optimization of the hydrogel-based BioMEMS. The parameter study is then conducted for analysis of the influence of the initial fixed charge density on the responsive characteristics of the ionic-strength-sensitive hydrogel including the ionic transport, electrical potential, and displacement.