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Prior to the arrival of the Spanish to Alta California, the area that is now San Gabriel was inhabited by the Tongva Native Americans, whom the Spanish called the Gabrieleño. The Tongva name for the San Gabriel region has been reconstructed as Shevaa.

Today a center for culture and art, the Mission San Gabriel Arcángel, founded by Father Junipero Serra, is the fourth of twenty-one California Missions, and is known as the "Pride of the California Missions."

The Mission San Gabriel Arcángel served a pivotal role in the colonial Spanish society, with many of the area's first Mexican settlers being baptized at the mission, including future governor Pio Pico, who was born in 1801 at the mission and baptized there the same year. He was appointed as California's governor twice, serving briefly in 1832 and again from 1845 through the Mexican-American War. Later in life, he was elected as a Los Angeles City councilman.The city of Pico Rivera was named to honor him as the last governor of California to be born in Mexico.

In 1853, a company of Army Engineers, who included the geologist William P. Blake, passed by the mission in search of the best route for an intercontinental railroad. Blake observed that the once great vineyards had fallen into wild disarray. Fences were in disrepair, and animals roamed freely through the property. But, the mission bells were ringing, and the church was still in use. Blake predicted, "I believe that when the adaptation of that portion of California to the culture of the grape and the manufacture of wine becomes known and appreciated, the state will become celebrated not only for its gold and grain, but (also) for its fruits and wines.

In the first United States census made in California in 1860, 586 people lived in San Gabriel. By the time of General Law Incorporation on April 24, 1913, the city's population had grown to 1,500.