Santa Ysabel Creek, the larger of the two source streams, rises in the northeastern corner of the San Dieguito watershed on the slopes of the Volcan Mountains. It creates Lake Sutherland before flowing out of the lake's dam and continuing west for the remainder of its approximately eleven-mile course. Santa Maria Creek, smaller, begins near Ramona and flows northward about seven miles through the Ramona Grasslands and Bandy Canyon before meeting Santa Ysabel Creek at the confluence that defines the beginning of the San Dieguito River proper.

This is the hydrology of a coastal California watershed in the mediterranean climate zone: modest permanent flow supplemented by significant winter rains, drying to a trickle or disappearing entirely in reaches during summer, with periodic flash floods during wet El Niño years that can fill the channel bank-to-bank. The river's gradient descends from the mountains through a series of canyons and valleys before crossing the coastal plain and entering the lagoon where it meets the sea.

Lake Hodges, created by a dam on the San Dieguito River above the coastal plain, captures a significant portion of the river's flow for municipal water supply. The David Kreitzer Lake Hodges Bicycle Pedestrian Bridge crosses the reservoir — one of the longest pedestrian suspension bridges in the United States, which gives the San Dieguito River the distinction of hosting both a significant piece of water infrastructure and an unusual piece of recreational infrastructure within the same watershed.

An Indian rancheria called San Dieguito appears in the records of the San Diego Mission in 1778 — a Kumeyaay settlement that the Spanish mission system acknowledged by naming it after the nearest mission and the river that ran nearby. The name San Dieguito attached itself to the rancheria, then to the river, then to the landscape more broadly, carrying through successive regimes of governance the memory of a Kumeyaay presence that the mission system was simultaneously documenting and destroying.

In 1840 or 1841, after the Mission Period ended, the name was applied to Rancho San Dieguito — one of the Mexican land grants that distributed former mission lands to private holders. The rancho name was later changed to Rancho Santa Fe in 1922 when the Santa Fe Railway, which had purchased the land planning to grow eucalyptus for railroad ties and discovered the wood too soft to hold spikes, pivoted to developing a planned residential community in the hills above the river's middle reaches.

The accumulation of names — Kumeyaay rancheria, Spanish mission designation, Mexican rancho, American railway venture, California community — compressed into the single toponym 'San Dieguito' is a small linguistic record of the valley's history: each culture that used the river left its mark on what the place was called without erasing what the previous culture had established.

The San Dieguito River must be crossed to move north along the California coast, and the history of how people have crossed it traces the evolution of transportation infrastructure. Camino Del Mar, the historic route that preceded U.S. Route 101, crosses the river near its mouth in Del Mar. The Southern California coast's rail corridor follows beside it: both the Coaster commuter rail and the Amtrak Pacific Surfliner cross the San Dieguito at Del Mar, their trains running on tracks that the Santa Fe Railway laid in 1887 and that have been continuously in service since.

Further upstream, Interstate 5 bridges the river at a grade-separated crossing, and a succession of smaller roads cross it as it winds through the inland communities. The San Dieguito River Park, managed by a joint powers authority, preserves a corridor along the river from the coast to the mountains as a trail and open space system — an attempt to maintain ecological and recreational connectivity in a watershed that has been heavily developed on its northern and southern edges.

The river's mouth opens into the San Dieguito Lagoon in Del Mar, where the Pacific meets the freshwater flow and creates the estuarine conditions that support coastal marsh habitat. The lagoon has been partially restored in recent decades as part of an effort to re-establish wetland function that was compromised by rail and road construction. The river that has given its name to so much of this landscape still reaches the sea.