A method of manufacturing a semiconductor device includes forming isolation layers in a first direction at trenches at isolation regions defined at a semiconductor substrate and forming gate lines in a second direction crossing the first direction over the isolation layers and active regions defined between the isolation layers, performing a dry-etch process to remove the isolation layers, and forming an insulating layer over the semiconductor substrate to form a first air gap extending in the first direction in the trenches and a second air gap extending in the second direction between the gate lines.