A religious census of the city in March of 1923 highlighted the fact that there were 435 Hispanics in the Cuero area, the majority claiming to be Catholic. Few of them were able to attend St. Michael’s for lack of space, language difficulties and other reasons. Therefore, Father Pallanche decided to provide a church for them. A block of land for this purpose was donated by W. H. Graham.

In the fall of 1924, Father Pallanche prepared to erect another church in Cuero. The new building is of Gothic design with a tower rising 75 feet. The church was placed under the patronage of Our Lady of Guadalupe and the first Mass was celebrated by Father Pallanche on February 22, 1925.

On April 25, 1925, Rev. Macario Lopez, a member of the Dominican Order came from Mexico to take charge of the new parish. The church was solemnly dedicated by Most Rev. A. J. Drossaerts, Bishop of San Antonio, on May 4, 1925.
When the Dominicans left in 1932 arrangements were made with the Missionaries of the Holy Family to take over the care of the parish and Father Herman Berg was sent in 1933.

In 1947 Father Niebel purchased an old army barracks at the local airport and moved the building to parish grounds. After remodeling was complete, the structure served as the parish hall and catechetical center. When the parish church was completely destroyed by fire on Christmas Day, 1948, the building also served as a temporary church.

On October 29, 1956, Auxiliary Bishop Stephen A. Leven officiated in the dedication of the new church. Encouraged by their pastor, Father August Otto, parishioners took pride in transporting and cutting rock for the wall of the church.
A new catechetical center was dedicated on April 5, 1964. In 1968 a new bell tower was erected and a new narthex was built at the entrance to the church with new stained-glass windows.

Following the departure of the Carmelite Sisters in 1969 their program of religious instruction and home visitation was taken up by the Missionary Catechist Sisters of the Immaculate Hearts of Jesus and Mary who came from Mexico on August 24, 1970. The interior of the church was remodeled in 1973 with the relocation of the altar at the side of the arrangement of the pews in a semicircle around the altar.

In 2002, after the retirement of Father Giorgi, who was the priest at Our Lady of Guadalupe for 20 years, St. Michael’s and Our Lady of Guadalupe shared one priest. The rectory at Our Lady of Guadalupe is now the place of residence for the priests and the main office merged with St. Michael’s Catholic Church.

In the fall of 2012, Our Lady of Guadalupe church began renovations to extend the foyer and add inside restrooms for the parish to use. Prior to the renovations, the only available restroom was a single stall located outside of the church beneath the bell tower. It remains today as a historical marker from the past. The bell tower today boasts a grotto to Our Lady of Guadalupe with a memory prayer garden in honor of loved ones from the parish community.
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n 2013 the rectory was renovated and a garage and patio area was added. In 2017 the interior of the current church received a fresh coat of paint, new carpet and new pews. There was also a new pavilion added to the parish hall along with a large BBQ pit area.