In cell transplantation therapy for spinal cord injury (SCI), grafted human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) mainly differentiate into neurons, forming synapses in a process similar to neurodevelopment. In the developing nervous system, the activity of immature neurons has an important role in constructing and maintaining new synapses. Thus, we investigate how enhancing the activity of transplanted hiPSC-NS/PCs affects both the transplanted cells themselves and the host tissue. We find that chemogenetic stimulation of hiPSC-derived neural cells enhances cell activity and neuron-to-neuron interactions in vitro. In a rodent model of SCI, consecutive and selective chemogenetic stimulation of transplanted hiPSC-NS/PCs also enhances the expression of synapse-related genes and proteins in surrounding host tissues and prevents atrophy of the injured spinal cord, thereby improving locomotor function. These findings provide a strategy for enhancing activity within the graft to improve the efficacy of cell transplantation therapy for SCI. Display omitted •Human iPSC-derived neurospheres are transplanted into the injured spinal cord•Excitatory DREADD is lentivirally induced to the graft before the transplantation•The grafts are consecutively and selectively stimulated after the transplantation•Motor function improves because of enhanced synaptic activity by the stimulation Kawai et al. transplant human iPSC-derived neural stem/progenitor cells in the sub-acute phase of rodent injured spinal cord, chemogenetically stimulating the graft repeatedly and selectively, and report improvements in motor functional recovery. Enhanced synaptic activity between the host and the graft is indicated to contribute to the functional recovery.