Fatigue due to physical exertion is a ubiquitous phenomenon in everyday life and especially common in a range of neurological diseases. While the effect of fatigue on limiting skill execution are well known, its influence on learning new skills is unclear. This is of particular interest as it is common practice to train athletes, musicians or perform rehabilitation exercises up to and beyond a point of fatigue. In a series of experiments, we describe how muscle fatigue, defined as degradation of maximum force after exertion, impairs motor-skill learning beyond its effects on task execution. The negative effects on learning are evidenced by impaired task acquisition on subsequent practice days even in the absence of fatigue. Further, we found that this effect is in part mediated centrally and can be alleviated by altering motor cortex function. Thus, the common practice of training while, or beyond, fatigue levels should be carefully reconsidered, since this affects overall long-term skill learning.