In 1821 Mexico declared its independence from Spain. During the Mexican Period of California's history the Law of Secularization (1833) was implemented, which resulted in the loss of the Salinan lands to the Californio rancheros. Nearly all of the mission ranchos were granted to Californio families, including Rancho Los Ojitos very near Mission San Antonio. Mission San Antonio was eventually abandoned by its last Franciscan Padre, Jose Gutierrez, in 1844.

In 1846 a war between the United States and Mexico resulted in Alta California becoming a U.S. territory. 

Father Doroteo Ambris was an Indian from Mexico who was ordained by the Franciscans in Santa Barbara in 1844.  After his ordination Father Ambris was the parish priest in Monterey during the war, and he occassionaly visited the Salinans at Mission San Antonio to celebrate the Mass. During the war the hacienda of Mariano Soberanes on Rancho Los Ojitos had been destroyed by American forces. Father Ambris complained to Colonel Richard Mason, the military governor of California, about the theft of tiles. Colonel Mason ordered that Soberanes could only take a limited number of tiles to repair his hacienda, but none for any new buildings.

California was admitted to the U.S. as the 31st State in 1850. At this time, as a result of the rapid influx of settlers during the gold rush, atrocities were being committed on native Americans in California. In 1851 Father Ambris became the parish priest at Mission San Antonio.  During the tenure of Father Ambris the Mission was officially deeded back to the Church by Abraham Lincoln. Father Ambris continued at the Mission until his death in 1882.  Upon his death the Mission was abandoned and fell into ruin. 

In the 1870s the rancho surrounding Mission San Antonio, Rancho Milpitas, came into the ownership of Faxon Atherton, under somewhat dubious conditions. California, American and Salinan settlers were evicted. Much later, in the early 1900s, this and many other ranch properties in the area were bought by William Randolph Hearst. Hearst built his ranch headquarters, what was to become known as the Hacienda, on Rancho Milpitas. In 1939 Hearst gave his ranch properties in the San Antonio Valley to the U.S. government for the establishment of Fort Hunter Liggett.