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On December 14, 1817, Mission San Rafael was established as an asistencia or "helper" mission to Mission Dolores in San Francisco. Since its original purpose was to care for the sick, it was named after St. Raphael the Archangel, the angel of bodily healing. Mission San Rafael was the 20^th mission in the chain of 21 missions established by the Spanish in Alta California beginning in 1769. The northern-most (and last) mission is Mission San Francisco de Solano, in what is now the town of Sonoma.

Initially, Mission San Rafael was one building, housing the sleeping quarters, cooking area and worship space. As the population expanded, dormitory sleeping areas and 2-story adobe work structures were added, where activities such as carpentry, sandal-making, blacksmithing and boat building were performed. Mission San Rafael was quite successful and, in the late 1820's when the Mission was at its peak, there were over 1000 people living here, largely composed of native American peoples. The Indians native to the area around Mission San Rafael were the Coast Miwoks.  

In 1834 the missions were secularized by Mexico and, in 1848 following the Bear Flag revolt, the buildings at Mission San Rafael began to deteriorate, were abandoned and eventually, torn down. By the 1850's, the number of natives living at the mission had declined to about 250.

A series of worship spaces were subsequently built on the site and, in 1949, a replica of the original mission was constructed adjacent to the 1919 parish church, on the approximate site of the original hospital mission. This replica building is referred to today as the Mission Chapel.