Fatigue is a temporary condition that arises as a result of intense and/or prolonged use of muscles and can affect skilled human performance. Therefore, the quantitative analysis of these effects is a topic of crucial interest in both ergonomics and clinical settings. This study introduced a novel protocol, based on robotic techniques, to quantitatively assess the effects of fatigue on the human wrist joint. A wrist manipulandum was used for two concurrent purposes: (1) implementing the fatigue task and (2) assessing the functional changes both before and at four time points after the end of the fatigue task. Fourteen participants completed the experimental protocol, which included the fatigue task and assessment sessions over 2 days. Specifically, the assessments performed are related to the following indicators: (1) isometric forces, (2) biomechanical properties of the wrist, (3) position sense, and (4) stretch reflexes of the muscles involved. The proposed fatigue task was a short-term, submaximal and dynamic wrist flexion/extension task designed with a torque opposing wrist flexion. A novel task termination criterion was employed and based on a percentage decrease in the mean frequency of muscles measured using surface electromyography. The muscle fatigue analysis demonstrated a change in mean frequency for both the wrist flexors and extensors, however, only the isometric flexion force decreased 4 min after the end of the task. At the same time point, wrist position sense was significantly improved and stiffness was the lowest. Viscosity presented different behaviors depending on the direction evaluated. At the end of the experiment (about 12 min after the end of the fatigue task), wrist position sense recovered to pre-fatigue values, while biomechanical properties did not return to their pre-fatigue values. Due to the wide variety of fatigue tasks proposed in the literature, it has been difficult to define a complete framework that presents the dynamic of fatigue-related changes in different components associated with wrist function. This work enables us to discuss the possible causes and the mutual relationship of the changes detected after the same task.