Its headwaters are at the Sierra Madre and runs a south and southwesterly course for about 261 kilometres (162 mi) until it drains into Manila Bay.

Southeast of Mount Arayat and the Pampanga River is the Candaba Swamp, covering an area of some 250 square kilometres (97 sq mi) absorbing most of the flood flows from the western slopes of a portion of the Sierra Madre and the overflowing of the Pampanga River via the Cabiao Floodway.

The flooding in September 2011 associated with Pedring (Typhoon Nesat) nearly swallowed all of Pampanga and southern parts of Bulacan.

Very catastrophic and exceptionally severe flooding in the river basin that engulfed the Central Luzon provinces of Pangasinan, Pampanga, Bulacan, Nueva Ecija, and Tarlac occurred in July and August 1972.

At the lower sections of the basin, where the Pampanga delta lies, the Pampanga River system divides into small branches, crisscrossed with fishponds to form a network of sluggish, tidal flats and canals, which eventually find their way to Manila Bay.