Therapeutic hypothermia is rapidly becoming an integral part of post-resuscitative care for post-cardiac arrest and neurotrauma patients. Despite the significant impact of thermoregulation on core temperature drop during rapid cooling, current mathematical models for thermoregulation have not been validated for hypothermic conditions. A geometrically accurate 3D model of an upper leg was developed by segmenting anatomical images from the visible human dataset into fat, muscle, bone, and blood vessels. Thermoregulation models from literature were implemented in the model. The numerical model results were compared with surface cooling experiments. There was a good agreement of simulation results with experimental data at 18 °C water immersion using existing models. However, at lower temperatures, the model parameter values needed to be significantly altered to account for cold-induced vasodilation in the superficial blood vessels and variation in muscle perfusion to match experimental observations. Additionally, results indicate that thermal mass has a dominant effect on cooling rate; therefore, uniform cooling over a large surface area will be more effective than targeted cooling of areas with superficial blood vessels. This study is the first to analyze the effects of thermoregulation in hypothermic conditions and identify unique thermoregulatory effects that differentiate hypothermic and normal conditions.