In 1791, Spaniard priests Manuel De Silva and Joseph Francisco Mariano Garza endeavored to spread the doctrines of Christianity among the native tribes along the Gulf Coast, now called Karankawa, with the added benefit of giving Spain a foothold in the frontier land. Establishing a truce of friendship among the coastal Indians, Garza tried to convince some to join the Mission of Rosario, but not wanting to leave their land, the Indians asked for the establishment of a Mission at the mouth of the Guadalupe River in the heart of Karankawa country. This was a place of protection when they were too closely pressed by their enemies. The site was already known as El Paraje Del Refugio (The Place of Refuge) and inspired by this, Father Silva gave the future Mission the title of Nuestra Senora Del Refugio (Our Lady of Refuge).
On February 4, 1793, the Mission was formally dedicated. While the Mission began with 138 recruits, many were reluctant and those who remained out of the Mission were antagonistic and sometimes hostile and dangerous. The Mission of Refugio remained at this location until April of 1794. During that month, Chief Fresada Pinta and his tribe raided and virtually destroyed the establishment. The Mission was eventually moved to the Rancho De Los Mosquitos, on the southwest side of the Guadalupe River in what
is now Refugio County. In January of 1795, it was moved further up the Mission River to the current townsite of Refugio. The Mission was used until 1830 when it was secularized and abandoned. Mission Refugio signifies the end of an era, as it was the last Spanish Mission built in Texas.