Between 1844 and 1887, Indianola grew to become a cosmopolitan port city that was second only to Galveston. Indianola became a port for trade and was the eastern terminus of the Chihuahua Road that traveled overland from the mines of Chihuahua city in Mexico. The mines of Mexico were primarily silver, but also included copper, zinc and lead. Other trails, such as the Santa Fe Trail, were long and difficult routes. The Chihuahua Road became popular as a more direct route, traveling from Indianola-Matagorda Bay, through San Antonio, along the Balcones Fault to the Rio Grande through Alpine and Marfa and then turned south to Mexico and up the Conchos River to Chihuahua city. The Chihuahua Road's several parts were known as the Indianola Road or Goliad Cart Road, the Old Spanish Trail and the Government or Military Road, and, in Mexico, El Camino del Rio Conchos.
By the 1850s, hundreds of wagons and Mexican carretas were outfitted in Indianola for the long and difficult journey across a wide variety of terrain. From 1844 to 1886, scores of towns in West Texas along the Chihuahua Trail were established as a result of trade between Indianola and Chihuahua, Mexico. The Chihuahua Road continued until 1877 when a hurricane destroyed Indianola and railroads replaced trails. Surveys have uncovered evidence of the trail and
land surveyor reports from this period have helped locate the exact route. For more than thirty years, the Chihuahua Trail played a dominant role in moving items of commerce, travelers and military supplies and personnel through this part of North America.