The site was first named La Lomita ("the hillock") by a rancher, José Antonio Cantu, who was granted the land by Spain in 1770. In 1851, a French merchant named René Guyard purchased the land. A devout Catholic, Guyard built the chapel in 1865, and in 1871 bequeathed it to the Missionary Oblates of Mary Immaculate.

Located between the Brownsville and Roma missions, La Lomita became an important stop for the Cavalry of Christ; it served some 65 area ranches, and traveling missionaries often stopped there to rest.

In 2018, the chapel became the subject of a dispute between the United States government and the Catholic Church due to the Trump administration's proposal to seize the chapel's land border wall between the U.S. and Mexico.

In 2019, the proposed seizure was blocked by a budget provision enacted by Congress.