Peripheral nerve injuries result in loss of motor, sensory and autonomic functions of the denervated limb, but are also accompanied by positive symptoms, such as hyperreflexia, hyperalgesia and pain. Strategies to improve functional recovery after neural injuries have to address the enhancement of axonal regeneration and target reinnervation and also the modulation of the abnormal plasticity of neuronal circuits. By enhancing sensory inputs and/or motor outputs, activity-dependent therapies, like electrostimulation or exercise, have been shown to positively influence neuromuscular functional recovery and to modulate the plastic central changes after experimental nerve injuries. However, it is important to take into account that the type of treatment, the intensity and duration of the protocol, and the period during which it is applied after the injury are factors that determine beneficial or detrimental effects on functional recovery. The adequate maintenance of activity of neural circuits and denervated muscles results in increased trophic factor release to act on regenerating axons and on central plastic changes. Among the different neurotrophins, BDNF seems a key player in the beneficial effects of activity-dependent therapies after nerve injuries.