Gadsden served Gen. Jackson both during the War of 1812 against the British Army, and, from 1816 to 1821, in protecting the southern U.S. border from raiders — Native Americans, maroons (escaped slaves and their descendants) — based in Spanish Florida.

As part of this effort, Jackson directed Gadsden, a member of the Army Corps of Engineers, to build a fort on the Prospect Bluff site.

As an engineer he directed the construction of the branch to Columbia, completed 1842, surveyed a proposed extension to the Ohio River, and helped promote the Memphis & Charleston Railroad, incorporated 1845 (completed in 1857, it was the first U.S. railroad link between the Atlantic and the Mississippi River, but long after Gadsden had turned his attention elsewhere).

He urged Georgia and South Carolina to abandon their rivalry and to "discover their true policy in the harmony of a free and unrestricted trade.

"[6] A late 1840s map shows this railroad would hypothetically have been by way of the southern route from Charleston through Georgia, Alabama, Mississippi, Louisiana, and Texas to El Paso, Texas, and then through Mexico to the coast, in what in a few years would be newly acquired American land, after the 1846–1848 war with Mexico.

He would use slave labor to build a railroad and highway, originating in either San Antonio or on the Red River, that would transport people to the California gold fields.

[9] A few months after this, Gadsden and 1,200 potential settlers from South Carolina and Florida submitted a petition to the California legislature for permanent citizenship and permission to establish a rural district that would be farmed by "not less than Two Thousand of their African Domestics".

The sectional crisis of the late 1850s and subsequent Civil War delayed construction of a proposed southern transcontinental railroad to California along the 32d parallel, just to the north of the Mexican border.

[12] At the same time, 1880–1882, the Atchison, Topeka and Santa Fe Railroad completed a transcontinental link through the Gadsden Purchase and then southwest to a terminus at the port of Guaymas, in the state of Sonora, Mexico.

The land bought by the Gadsden Purchase contained the site of Arizona's second largest city, Tucson, a one-time Spanish presidio town, the minor cities and towns of Casa Grande, and Yuma, Arizona, Lordsburg, Deming, New Mexico, and New Mexico's second largest metro area at Las Cruces, New Mexico, in the Mesilla Valley, and it defined the status of the area north of the Gila River, that later became the metropolitan area of Phoenix, Scottsdale, Mesa, Glendale, and Tempe, Arizona.