Physical exercise (PE) has become an essential tool for different rehabilitation programs. High-intensity exercises (HIEs) have been demonstrated to provide better results in general health conditions, compared with low and moderate-intensity exercises. In this context, monitoring of a patients’ condition is essential to avoid extreme fatigue conditions, which may cause physical and physiological complications. Different methods have been proposed for fatigue estimation, such as: monitoring the subject’s physiological parameters and subjective scales. However, there is still a need for practical procedures that provide an objective estimation, especially for HIEs. In this work, considering that the sit-to-stand (STS) exercise is one of the most implemented in physical rehabilitation, a computational model for estimating fatigue during this exercise is proposed. A study with 60 healthy volunteers was carried out to obtain a data set to develop and evaluate the proposed model. According to the literature, this model estimates three fatigue conditions (low, moderate, and high) by monitoring 32 STS kinematic features and the heart rate from a set of ambulatory sensors (Kinect and Zephyr sensors). Results show that a random forest model composed of 60 sub-classifiers presented an accuracy of 82.5% in the classification task. Moreover, results suggest that the movement of the upper body part is the most relevant feature for fatigue estimation. Movements of the lower body and the heart rate also contribute to essential information for identifying the fatigue condition. This work presents a promising tool for physical rehabilitation.