In 1776 certain gentiles, who were hostile to some Indians that were sheltered by the padres, attacked the Mission by discharging burning arrows upon the tule roof of the buildings, and everything was destroyed, save the church and the granary.  Rivera came at once, captured two of the ringleaders, and sent them for punishment to the Monterey presidio.  The success of the gentiles led them to repeat their attacks by setting fire to the Mission twice during the next ten years, and it was these calamities that led one of the San Luis padres to attempt the making of roof tiles.  Being successful, it was not long before all the Missions were so roofed.

In 1794 certain of the neophytes of San Luis and La Purisima conspired with some gentiles to incite the Indians at San Luis to revolt, but the arrest and deportation of fifteen or twenty of the ringleaders to Monterey, to hard labor at the presidio, put a stop to the revolt.

Padres Lasuen and Tapis both served here as missionaries, and in 1798 Luis Antonio Martinez, one of the best known of the padres, began his long term of service at San Luis.  In 1794 the Mission reached its highest population of 946 souls.  It had 6500 head of cattle and horses, 6150 sheep.  In 1798 it raised 4100 bushels of wheat, and in this same year a water-power mill was erected and set in motion.  San Luis was also favored by the presence of a smith, a miller and a carpenter of the artisan instructors, sent by the king in 1794.  Looms were erected, and cotton brought up from San Blas was woven.  A new church of adobes, with a tile roof, was completed in 1793, and that same year a portico was added to its front.

In 1830 Padre Martinez was banished to Madrid, and at this time the buildings at San Luis were already falling into decay, as the padre, with far-seeing eye, was assured that the politicians had nothing but evil in store for them.  Consequently, he did not keep up things as he otherwise would have done.  He was an outspoken, frank, fearless man, and this undoubtedly led to his being chosen as the example necessary to restrain the other padres from too great freedom of speech and manner.

In 1834 San Luis had 264 neophytes, though after secularization the number was gradually reduced until, in 1840, there were but 170 left.  The order of secularization was put into effect in 1835 by Manuel Jimeno Casarin.  The inventory of the property in 1836 showed $70,000.  In 1839 it was $60,000.  In 1840 all the horses were stolen by “New Mexican traders,” one report alone telling of the driving away of 1200 head.  The officers at Los Angeles went in pursuit of the thieves and one party reported that it came in full sight of the foe retiring deliberately with the stolen animals, but, as there were as many Americans as Indians in the band, they deemed it imprudent to risk a conflict.

In December of 1846, when Fremont was marching south to co-operate with Stockton against the Southern Californians, San Luis was thought to harbor an armed force of hostiles.  Accordingly Fremont surrounded it one dark, rainy night, and took it by sudden assault.  The fears were unfounded, for only women, children, and non-combatants were found.