The aim of the present study was to compare the development and etiology of neuromuscular fatigue of the knee extensor (KE) and plantar flexor (PF) muscles during repeated maximal voluntary isometric contractions (MVIC) between children and adults. Twenty-one prepubertal boys (9-11 years) and 24 men (18-30 years) performed two fatigue protocols consisting in a repetition of 5-s isometric MVIC of the KE or PF muscles interspersed with 5-s passive recovery periods until MVIC reached 60% of its initial value. The etiology of neuromuscular fatigue of the KE and PF muscles was investigated by means of non-invasive methods such as the surface electromyography, single and doublet magnetic stimulation, twitch interpolation technique and NIRS. The number of repetitions performed was significantly lower in men (15.4 ± 3.8) than boys (38.7 ± 18.8) for the KE fatigue test. In contrast, no significant difference was found for the PF muscles between boys and men (12.1 ± 4.9 and 13.8 ± 4.9 repetitions, respectively). Boys displayed a lower reduction in potentiated twitch torque, low-frequency fatigue and muscle oxygenation than men whatever the muscle group considered. In contrast, voluntary activation level and normalized EMG data decreased to a greater extent in boys than men for both muscle groups. To conclude, boys experienced less peripheral and more central fatigue during repeated MVICs than men whatever the muscle group considered. However, child-adult differences in neuromuscular fatigue were muscle-dependent since boys fatigued similarly to men with the PF muscles and to a lower extent with the KE muscles than men.