The river is approximately 510 kilometres (320 mi) long and passes through or borders the states of Mexico, Hidalgo, Querétaro, San Luis Potosí, Tamaulipas, and Veracruz.

It runs northward, forming the state border between Hidalgo and Querétaro as it moves toward San Luis Potosí, before turning eastward to carve a deep canyon through the Sierra Madre Oriental.

The Pánuco winds another 172.5 km through the coastal lowlands, joined from the south by the Topila and from the north by the Tamesí, before emptying into the Gulf of Mexico at Tampico–Ciudad Madero, Tamaulipas.

The watershed of the Pánuco and its tributaries drains portions of Tamaulipas, San Luis Potosí, Guanajuato, Querétaro, Hidalgo, Mexico, Puebla, and Veracruz.

In 1519, during his cartographic expeditions along the western coast of the Gulf of Mexico, Spanish explorer Alonso Álvarez de Pineda established a settlement on the river, which he named Las Palmas, though it was abandoned after he was killed in battle with indigenous peoples living nearby.

[4] There are many endemics: six Nosferatu cichlid species, five Tampichthys minnows, nine "northern swordtails" (genus Xiphophorus), three Gambusia species, two Ictalurus catfish, the bluetail goodeid (Ataeniobius toweri), dusky splitfin (Goodea gracilis), relict splitfin (Xenoophorus captivus), pygmy shiner (Notropis tropicus), checkered pupfish (Cualac tessellatus), broadspotted molly (Poecilia latipunctata), Tamasopo cichlid (Herichthys tamasopoensis), Calabazas shiner (Notropis calabazas) and fleshylip buffalo (Ictiobus labiosus).