Spanish missionary Pedro Font scouted this site in March 1776, traveling with explorer Juan Bautista de Anza through the Bay Area. On October 9, 1776, Fathers Francisco Palou and Pedro Benito Cambron dedicated a small chapel near what is now the intersection of Camp and Albion Streets. They named it for Francis of Assisi, founder of their Franciscan order. But the place became known by the creek that watered it: Arroyo de Nuestra Senora de los Dolores, Our Lady of Sorrows Creek. The mission predates American independence by three months. Members of the local Ramaytush Ohlone tribe first entered the mission in 1785, and they would provide the labor that built the permanent church.

Construction began in 1788. By 1790, the adobe walls stood complete, plastered and whitewashed, waiting for their redwood roof beams and painted ceiling. When the church was completed and dedicated on August 2, 1791, its ceiling displayed traditional Ohlone designs painted in vegetable dyes, a haunting collaboration between colonizer and colonized. The mission system extracted a terrible cost: over 5,000 Native Americans died from disease and other causes at Mission San Francisco. By 1842, only eight remained. The Mexican Secularization Act of 1833 had stripped the missions of their vast lands, and the California Gold Rush of 1848 would transform San Francisco into something the padres never imagined.

The 1906 earthquake destroyed the brick Gothic Revival church that the Archdiocese had built beside the original adobe in 1876. The great fire that followed threatened to consume both buildings. Firefighters made a desperate choice: they dynamited the convent and School of Notre Dame across the street to create a firebreak. The gamble worked. The adobe survived with damage; architect Willis Polk restored it in 1917. The Mission Dolores Basilica rose between 1913 and 1918 to replace the destroyed brick church, and Pope Pius XII designated it a minor basilica in 1952.

The cemetery and gardens behind the mission contain grave markers dating from 1830 to 1898. An Ohlone Indian ethno-botanic garden grows native plants that would have been familiar in 1791, while a rose garden maintained by the Golden Gate Rose Society adds color. A cast stone sculpture of Junipero Serra by Arthur Putnam, completed in 1909 and installed in 1918, depicts the founder of the California mission system in his Franciscan robes. The Mission Dolores Basilica contains a stained glass window of Francis of Assisi created by German artist Franz Xaver Zettler. Inside, a mural depicts the Sacred Hearts of Jesus and Mary, along with a rooster symbolizing Christ's resurrection.

Three California Historical Landmarks cluster around Mission Dolores: the site of the original chapel and Dolores Lagoon, the 1800 hospice outpost in San Mateo that served travelers, and El Camino Real itself, the royal road connecting the California missions. The Archdiocese of San Francisco has operated the mission since 1857. In a city famous for reinvention, for building and burning and building again, the adobe chapel stands as it did when the United States was a collection of Atlantic seaboard colonies and California was the farthest reach of Spanish ambition. The thick walls still hold their secrets, still bear witness.