This study presents an in vivo model of functional and vascularized human brain organoids by transplanting human brain organoids into the adult mouse brain. The organoid grafts showed progressive neuronal differentiation, maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Electrophysiological recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This model may facilitate disease modeling under physiological conditions.This study presents an in vivo model of functional and vascularized human brain organoids by transplanting human brain organoids into the adult mouse brain. The organoid grafts showed progressive neuronal differentiation, maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Electrophysiological recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This model may facilitate disease modeling under physiological conditions.