The mainstem starts east of Rocky Mountain in the Cleveland National Forest and flows generally south-southwest.

From the base of Henshaw Dam, the river winds west along the foot of the Palomars, followed by California State Route 76.

It leaves the canyon at the wide and spacious Pauma Valley, where it becomes a wash surrounded on both sides by agricultural fields.

The river turns west, passing Pala, flowing through a patchwork of privately owned, government-owned and Native American lands.

The first European land exploration of Alta California, the Spanish Portolà expedition, stopped at the river not far from the coast for two nights on its way north, July 18–19, 1769.

Franciscan missionary Juan Crespi noted in his diary, "...we descended to a large and beautiful valley, so green that it seemed to us that it had been planted.

The 2010 Rockstar Games release "Red Dead Redemption" features a river inspired by the San Luis Rey.