The Spanish began using the trail in 1690, when Alonso de León, a Spanish explorer, crossed the Rio Grande heading to eastern Texas to establish missions. He followed routes previously used as Indian trails and trade routes.

The El Camino Real de los Tejas (The Royal Road) was established by Spanish explorers and missionaries in the late 17th century. The primary figure credited with establishing the first major corridor was Alonso de León, the Spanish governor of Coahuila, who led several expeditions into East Texas between 1686 and 1690 to search for and destroy French settlements. His path followed ancient indigenous trade routes that had been used by Native American tribes for centuries. Over time, the trail was expanded by other Spanish figures like Domingo Ramón and the Marqués de San Miguel de Aguayo to connect a network of missions and presidios (forts) from Mexico City to the East Texas border and into present-day Louisiana. In 2026, the trail is recognized as a National Historic Trail, celebrating its legacy as a vital artery of immigration, trade, and cultural exchange that helped shape the early identity of Texas and the American Southwest.