Disruption of the axons of the corticospinal tract (CST) following traumatic injuries, such as spinal cord injury and stroke, results in motor functional deficits. Here, Liu et al. show that adeno-associated virus-assisted co-expression of two soluble proteins — insulin-like growth factor 1 and osteopontin — in cortical neurons stimulated CST regrowth and improved functional recovery in two CST-related injury mouse models. Additional treatment of these mice with 4-aminopyridine-3-methanol (a voltage-gated potassium channel blocker that increases axon conduction) further improved CST-dependent behavioural tasks.