The ability of the adult brain to form new connections in areas denervated by a lesion (axonal sprouting) is more widespread than previously thought, but mechanisms remain unknown. We have previously demonstrated an unexpected, robust axonal sprouting of contralateral corticostriatal neurons into the denervated striatum after ischemic cortical lesions. We now take advantage of marked differences in the degree of axonal sprouting from contralateral homotypic cortex after two types of cortical lesions to define the role of neuronal activity in this response. Thermal–ischemic lesions (TCL) of sensorimotor cortex, which induce axonal sprouting, produced two sequential patterns of low-frequency, synchronized neuronal activity that are not seen after similarly sized aspiration lesions, which do not induce axonal sprouting. An early rhythm of synchronous neuronal activity occurred in perilesion cortex on day 1 after lesion, with a frequency range of 0.2–2 Hz. A later pattern of activity occurred on days 2 and 3 after lesion, with a frequency range of 0.1–0.4 Hz. This second rhythm synchronized neuronal activity across widespread areas, including the cortical areas that contain the cell bodies of the sprouting axons. TTX was used to block this patterned neuronal activity and determine whether axonal sprouting was prevented. Chronic TTX infusion into the lesion site blocked the synchronous neuronal activity after TCL as well as axonal sprouting. Thus, both after different types of lesions and in the blockade experiments axonal sprouting was strongly correlated with synchronous neuronal activity, suggesting a role for this activity in anatomical reorganization after brain lesion in the adult.