The mountain range begins at Pico de Orizaba, and extends in a southeasterly direction for 300 km (190 mi) until reaching the Isthmus of Tehuantepec.

The Blanco River rises at the northern end of the range, and cuts a large canyon through the Sierra on its way to the Gulf of Mexico.

The Papaloapan River drains much of the northern and central Sierra, including both the eastern and western slopes of the range, before emptying into the Gulf of Mexico.

[1] The Sierra Madre de Oaxaca pine-oak forests ecoregion lies above 1,600 metres (5,200 ft) in elevation.

The humid Oaxacan montane forests ecoregion lies below 1,600 metres (5,200 ft) in elevation, on the eastern slopes above the Veracruz lowlands.

To the east, the xeric Tehuacan Valley matorral ecoregion occupies the Tehuacan valley to the northwest, the Balsas dry forests ecoregion occupies the upper basin of the Santo Domingo River, which lies in the rain shadow of the Sierra Madre de Oaxaca.