By harvesting thermal energy from human skin, self-powered wearable electronics have the potential to overcome the limitations of battery power, enabling long-term continuous operation. Flexible thermoelectric generators (TEGs) that can form a conformal contact with heat sources of any shape are critical for self-powered wearables. Nevertheless, practical implementations and efficient harvesting of heat energy from the human body are still hindered by factors that significantly diminish the power output of flexible TEGs. In this work, we present a design framework and computational platform optimized for modelling the harvesting of skin-heat energy using organic-based flexible thin-film TEGs. First, a three-dimensional numerical model based on the finite element method (FEM) has been developed, which enables the study and optimization of organic-based film thermoelectric (TE) device and TEG parameters, such as width, length, thickness, and interconnection dimensions, to maximize performance. Then, the optimized flexible TEG has been used to investigate the effect of human skin on wearable device applications in different parts of the body and environmental conditions. Mechanical interlayers designed to control various interface functions can alter junction resistances, leading to structures that are either highly conductive or insulating. Soft heat conductor (SHC) and soft heat insulator (SHI) layers are embedded to enhance the thermal interfaces and temperature difference across the TEG. As a result, embedding these soft heat layers can increase the temperature difference (ΔT) and open circuit voltage (VOC) along the TEG by ∼30 % over conventional flexible thin-film TEGs, while preserving mechanical softness and flexibility. Additionally, a study on the impact of the skin/TEG matching and heat flux at the skin/TEG interface is presented. Lastly, using a state-of-the-art post-treated poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) film-based TEG device model, we determined the maximum power output obtainable on various parts of the human body under three distinct environmental conditions (cold, room, and hot temperatures).