Life at the mission flourished until 1834, when secularization took place and the mission was turned over to the Mexican government.

The Luiseno Indians were given Mexican citizenship, but the Mission holdings were confiscated by new settlers. 

In 1846, Governor Pio Pico sold the Mission for $2,437.  The property was divided, its buildings stripped of material goods by area settlers and left to ruin. 

The mission buildings were occupied between 1846 and 1865 by various U.S. military troops, including the Battalion of Mormon Volunteers.  In 1850, California became the 34th state of the union and the remaining mission lands were incorporated into the United States. 

In 1853 the federal government refused to recognize Mission Indian land claims.  However, a separate claim was recognized to church buildings, cemeteries and gardens that had been designated for parish use in the various secularization decrees. 

On March 18, 1865, less than one month before his assassination, President Abraham Lincoln signed a proclamation returning Mission San Luis Rey to ecclesiastical control.