Padre Island was first visited in 1519 by the Spanish explorer Alonso Álvarez de Piñeda, who called it Isla Blanca. It was later renamed for a priest, Padre José Nicolás Ballí, who set up a ranch there in 1804 and preached to the local Karankawa Indians. The island consists of miles of white sandy beaches as well as dunes, grasslands, wetlands, and tidal flats. A wide variety of shorebirds, including pelicans, plovers, and egrets, inhabits the island; it is also a primary stop for migratory birds, particularly the peregrine falcon. South Padre Island is a popular destination for college students during spring break.

In 1962 much of the island was designated a national seashore. Its area of 203 square miles (526 square km) extends over a 70-mile (115-km) stretch of the island's central portion. It contains the longest remaining stretch of undeveloped barrier island in the United States; only its northern tip is inhabited. There is camping at Malaquite Beach. The national seashore participates in a sea turtle nesting program in which eggs are collected from nests to hatch in an incubator and baby turtles are released into the gulf.