Equipped with a two-dimensional topological structure, a group of masses, springs and dampers can be demonstrated to model the internal dynamics of a thin-film transistor (TFT). In this paper, the two-dimensional Mass-Spring-Damper (MSD) representation of an inverted staggered TFT is proposed to explore the TFT’s internal stress/strain distributions, and the stress-induced effects on TFT’s electrical characteristics. The 2D MSD model is composed of a finite but massive number of interconnected cellular units. The parameters, such as mass, stiffness, and damping ratios, of each cellular unit are approximated from constitutive equations of the composite materials, while the electrical properties of the inverted staggered TFT are characterized by utilizing an electro-mechanical coupling relation derived from the quantum mechanics. TFTs are often used in biomedical sensors/transducers attached to human skins, and, for the purpose of simulation and validation, the boundary conditions on the interface between the TFT and the human skin were modeled as a spatially distributed sinusoidal excitation with a frequency of 50 Hz, assuming the TFT thickness is more than tens of microns. The fidelity of the 2D MSD structure in the modeling of an inverted staggered TFT is verified by comparing its simulated total displacement field with that of a finite element analysis (FEA) model. The advantages of the MSD model include a dramatic reduction in memory use by up to 60% and faster computation times that are up to 80% lower. More importantly, the MSD model is better suited than FEA to many problems in accurate tissue modeling for medical applications, for which FEA is becoming a bottleneck. This work develops a novel modeling approach, which can be extended to other types of flexible thin film transistors.