In July of 1769, Father Serra dedicated this site as the first mission. This was to be the first of three missions planned by the Spanish, one at San Diego, one at Monterey, and another to be dedicated somewhere in between. It was very important to them to be able to travel from one to the other within a day's time via horseback. Eventually this was possible because of the placement of all twenty-one missions.

After their journey from Mexico, the settlers became very ill and were only able to build small, crude shelters. The Indians were not happy about this invasion by strange people. It took some time for Father Serra to be able to convert a few of the natives. In 1774, the original site was abandoned for a better site six miles up the river.

San Diego Mission, first of the twenty-one, was not among the most important of all twenty-one missions. Even though it was the first to be built it wasn't able to feed all of the population in and around the area. They had water, soil and labor problems. The water was either scarce or they had too much. It didn't seem to balance out in order to raise crops for the people.

In 1776, Indians didn't want the Spanish on their land so they attacked the mission by setting fire to it. This did not deter the Spanish, but instead encouraged them to bolster their military presence in the presidios. There was never again such a severe raid by Indians on a mission, though many attacks on missions did occur throughout the period.

The mission was named for St. Didacus of Alcalá, Spain. Vizcaíno had originally named the bay for him in 1602 St. Didacus was a Franciscan who dedicated his life to teaching religion and taking care of sick people. He was beatified into sainthood in the year 1588.