In a letter to the King, Pineda drew a map with the dot label of "Isla Blanca" (White Island), claiming the inhabited coastal land, but making reference of a mysterious Native American cannibalistic tribe; the Karankawa Indians. Before the Karankawan, it is believed that the region was inhabited by Archaic Indians between 2700 to 1000 B.C., and later the Karankawan, Coahuiltecan Indians took their place.

The name of South Padre Island is linked to its history, being the name of Father José Nicolás Ballí (Padre Balli), a secular Catholic priest and early settler, born in Reynosa Tamaulipas, Mexico, eldest of three sons of José María Balli Guerra and Rosa María Hinojosa Benavides de Ballí, daughter of Spanish aristocrats.

Rosa María Hinojosa became a rancher known as "La Patrona", being the first "cattle queen" in the so-then Mexican state of Texas. As former settlers, Rosa María's family received priority rights to extensive land grants and public offices, and his father was appointed alcalde in 1767.

It is believed that Rosa María was educated in Reynosa, by the parish priest, and when she married José Maria Balli, a captain of the militia, the Hinojosa family was part of the elite group of wealthy families controlling the jurisdiction. Later, Father Balli was granted with the coastal island named Padre Island in his honor

Padre Balli led an active religious and civic life in South Texas and the bordering state of Tamaulipas as an explorer, colonizer, rancher and missionary in the over one-million acres of land that his parents owned in the Reynosa, Camargo, and Matamoros in Tamaulipas, and all the lower Rio Grande Valley in Texas.

After completion of his secondary and ecclesiastical education in the Conciliar Catholic Seminary in Monterrey, Nuevo León. He was probably ordained between 1790 and 1791, beginning to conduct religious services in the haciendas and villas in the lower Rio Grande Valley, establishing later in Matamoros where he was a secular priest in Nuestra Señora del Refugio Mission.

Padre Ballí requested to his father a clear title to the property of Padre Island in 1827, becoming the first settler on the island and brought in more and more families. Padre Balli found the Karankawa Indians living in the island and built the first church for their conversion and benefit of the new settlers

After founding El Rancho Santa Cruz de Buena Vista in the north of the island's southern tip, Padre Balli kept cattle, horses, and mules for the people. The priest died on April 16, 1829, being buried near Matamoros. Incidentally, his title to the island was granted him posthumously on December 15, 1829, issued jointly in the name of the Padre and his nephew Juan José Ballí to whom Padre Balli wanted to reward with half for his support and help.

During the American Civil War, confederate loyalists began to hide their valuable possessions in the sands of Padre Island, in Balli's Rancho Santa Cruz, transformed into John Singers home by1847. Pro-Union Singers buried approximately $62,000 in jewelry and coins before escaping the area from the Civil War in 1861.

The Union returned after the War, but the sands concealed their hidden treasures. Today it is believed that the coins and jewelry are still buried in a South Padre Island's dune, probably on Money Hill. Perhaps only a legend, since another version says that such treasure was being sent to Spain from Mexico when the ship wrecked by storms at Padre Island dragged the valuables to the sand.

With the turn of the century, history became to develop more quickly beginning with the first recreational facilities, fishing spots and businesses. Many celebrities were attracted to the area, such as President Harding. In the 1940s, the US Air Force established an Air Base nearby the actual Cameron County Airport.

Paramount Pictures shot in Padre Island a WWII propaganda film in 1943, "Aerial Gunner" starring Robert Mitchum. In the 1950s, the completion of the Queen Isabella Causeway (today Queen Isabella State Fishing Pier) helped to develop the tourist industry. In 1954, a $2.2 million swing bridge was constructed connecting Port Isabel to South Padre Island.

The early 1960s brought a large portion of the Island closed to the public under the National Park Service, open again in 1962. Later in 1966, the Hurricane Beulah, destroyed Port Isabel, the gateway to the island. By 1980 Padre Island was labeled the "best kept secret" of the state of Texas and one the top 10 beaches in the nation until the present.