To elucidate the irreversible photoreaction of green fluorescent protein (GFP), we have theoretically analyzed hydrogen-bonding networks and distributions of water molecules around a chromophore (CRO) of GFP before and after photoactivation. Our molecular dynamics simulation clearly shows that such irreversibility arises from the migration of water molecules to the hollowed out region due to the reorientation of amino acid residues together with the disappearance of hydrogen-bonding networks around the CRO.