In Juan Bautista de Anza's second trip (1775–1776) he returned to California with 240 friars, soldiers and colonists with their families. They took 695 horses and mules and 385 Texas Longhorn cattle with them. The approximately 200 surviving cattle and an unknown number of horses (many of each were lost or eaten along the way) started the cattle and horse raising industry in California. In California the cattle and horses had few predators and plentiful grass in all but drought years. They essentially grew and multiplied as feral animals, doubling roughly every two years.

The expedition started from Tubac, Arizona, on October 22, 1775, and arrived at San Francisco Bay on March 28, 1776. There they selected the sites for the Presidio of San Francisco, followed by a mission, Mission San Francisco de Asís (Mission Dolores), within the future city of San Francisco, which took its name from the mission. He did not establish the settlement; it was established later by José Joaquín Moraga. While returning to Monterey, he located the original sites for Mission Santa Clara de Asis and the town of San José de Guadalupe (modern day San Jose, California), but again did not establish either settlement. Today this route is marked as the Juan Bautista de Anza National Historic Trail.