The missions were secularized in 1834, and Jose Joaquin Ortega and Edward Stokes received the Rancho Santa Ysabel Mexican land grant in 1844.

In 1846, General Stephen W. Kearny and the "Army of the West" made camp on the rancho on their way to the Battle of San Pasqual following this road.

Jean Baptiste Charbonneau, son of Sacagawea, camped at the Mission in 1847 after guiding the Mormon Battalion from New Mexico to San Diego.

John Russell Bartlett, an American traveller who passed by the Mission proper in 1852, noted that the facility consisted of little more than a roofless church and a few simple huts; nothing remains of the original structures due to neglect over the years.

After three acres of the original Mission compound are returned to the Roman Catholic Church, Father Joseph Exalaphat Lapointe, a French-Canadian missionary, came to Santa Ysabel in 1903 to work with the locals.

The day after they disappeared, a local named Jose Maria Osuna found the clappers (bell ringers) and took them home for safekeeping.

In 1993, a local molder named Ed Schwaesdall and his son John struck a new bell (made mostly of brass and copper) and donated it to the Mission in honor of the installation's 175th anniversary.