In 1769, he accompanied Gaspar de Portolá on his expedition to California. When the party reached San Diego, Serra stayed behind to start the Mission San Diego de Alcala. When Monterey was reached and Mission San Carlos Borromeo founded, Serra remained there as president of the Alta California missions. In 1771 he moved the mission to Carmel, which became his headquarters. Under his presidency were founded Mission San Antonio de Padua, Mission San Gabriel Arcángel, Mission San Luis Obispo, Mission San Juan Capistrano, Mission San Francisco de Asís, Mission Santa Clara de Asís and Mission San Buenaventura.
In 1784, at the age of 70, Father Serra died at Mission San Carlos Borromeo and is buried there under the sanctuary floor.
Serra has been declared a "Blessed" by the Catholic Church, and many are pushing for his canonization. However, Native American groups are opposed to this, on the grounds that his missions enslaved their people.