Greater Santiago is wedged between two mountain ranges, the Andes and the coastal cordillera. Although it's made up of some 37 comunas (districts), most sights and activities are concentrated in a few of the central neighborhoods.

East–west thoroughfare Av O'Higgins (better known as the Alameda) is the city's main axis; east of Plaza Italia it becomes Av Providencia and then Av Apoquindo. Metro Línea 1 runs under it for much of its length. Flowing roughly parallel to the north is the highly polluted Río Mapocho, which effectively acts as the border between downtown and the northern suburbs.

Three climbable hills punctuate the otherwise-flat cityscape: Cerro San Cristóbal (a major open-space park), Cerro Manquehue (home to great urban hiking routes) and the smaller Cerro Santa Lucía.