Brain-machine interfaces (BMIs) provide a framework for studying cortical dynamics and the neural correlates of learning. Neuroprosthetic control has been associated with tuning changes in specific neurons directly projecting to the BMI (hereafter referred to as direct neurons). However, little is known about the larger network dynamics. By monitoring ensembles of neurons that were either causally linked to BMI control or indirectly involved, we found that proficient neuroprosthetic control is associated with large-scale modifications to the cortical network in macaque monkeys. Specifically, there were changes in the preferred direction of both direct and indirect neurons. Notably, with learning, there was a relative decrease in the net modulation of indirect neural activity in comparison with direct activity. These widespread differential changes in the direct and indirect population activity were markedly stable from one day to the next and readily coexisted with the long-standing cortical network for upper limb control. Thus, the process of learning BMI control is associated with differential modification of neural populations based on their specific relation to movement control.