The historic route is overseen by both the National Park Service and the U.S. Bureau of Land Management with aid from the El Camino Real de Tierra Adentro Trail Association (CARTA).

[5] Traveling north through San Miguel de Allende, Guanajuato, the road's northern terminus is located at Ohkay Owingeh, New Mexico.

Long before Europeans arrived, the various indigenous tribes and kingdoms that had arisen throughout the northern central steppe of Mexico had established the route that would later become the Camino Real de Tierra Adentro as a major thoroughfare for hunting and trading.

In April 1598, a group of military scouts led by Juan de Oñate, the newly appointed colonial governor of the province of Santa Fe de Nuevo México, became lost in the desert south of Paso del Norte while seeking the best route to the Río del Norte.

The conducta consisted of wagon caravans that departed every three years from Mexico City to Santa Fe along the Camino Real de Tierra Adentro.

The villa of San Felipe el Real (today city of Chihuahua), established in 1709 to support the surrounding mines, became the most important commercial center and financial area along this segment.

The villa of San Felipe Neri de Alburquerque (present-day Albuquerque, New Mexico) was founded in 1706 and it also became an important terminal.

Because of its defensive position on the Camino Real, the Villa de Alburquerque became the center of commercial exchange between Nuevo México and the rest of New Spain during the 18th century, trading cattle, wool, textiles, animal skins, salt, and nuts.

In 1765, the population of El Paso del Norte was estimated to be 2,635 inhabitants, which created what was then the largest urban center on the northern border of New Spain.

In the 18th century, the Spanish Crown authorized the establishment of fairs along the Camino Real to promote commerce (although some form of these had already been existing for some time prior).

The Fair de Taos was also an important annual event where the Comanches and the Utes traded weapons, ammunition, horses, agricultural products, furs, and meats with the Spanish.

Spain at the same time maintained a monopoly on the products of its northern provinces, thus no trade occurred with the French colony of Louisiana.

In 1786, the nephew of José de Gálvez, Bernardo de Gálvez, viceroy of New Spain published his "Instructions" which included three strategies for dealing with the Natives: Continuing the military pressure on hostile and unaligned tribes; Pursuing the formation of alliances with friendly tribes; and promoting economic dependency with those natives who had entered into peace treaties with the Spanish Crown.

In 1807, American merchant and military agent Zebulon Pike was sent to explore the southwestern borders between the US and New Spain with the intention to find a trail to bring US commerce into Nuevo México and Nueva Vizcaya (Chihuahua).

Pike was captured on 26 February 1807 by the Spanish authorities in northern Nuevo México, who sent him on the Camino Real to the city of Chihuahua for interrogation.

The Camino Real maintained an important role in this period, since travelers brought communication about the events that were taking place in the center of the country to the towns and villages of the internal provinces.

For example, after the liberator Miguel Hidalgo y Costilla launched the war of independence, he used the road to retreat from the Battle of the Bridge of Calderón fought on the banks of the Calderón River 60 km (37 mi) east of Guadalajara in present-day Zapotlanejo, Jalisco, northward, eventually arriving at the Wells of Baján in Coahuila where he was captured and executed by royal forces.

At first, US merchants were arrested and imprisoned for bringing contraband into Mexican territory; however, the growing economic crisis in northern Mexico gave rise to an increased tolerance of this type of trade.

In 1846, the dispute over the Texas-Mexico border with the United States gave rise to the subsequent invasion by US military forces and the Mexican–American War began.

One of these forces was commanded by the general Stephen Kearny, who traveled by the Santa Fe Trail to seize the capital of New Mexico.

Another of the forces commanded by Colonel Alexander William Doniphan defeated a small group of Mexican contingents on the Camino Real in the Los Brazitos area south of what is now Las Cruces, New Mexico.

During 1846–1847, the Camino Real de Tierra Adentro became a path of continuous use, with American forces using it to travel into the interior of Mexico.

One of the soldiers provided an estimate of the population of several cities along the Camino, including: Algodones, New Mexico, with 1,000 inhabitants; Bernalillo with 500; Sandía Pueblo with 300 to 400, Albuquerque without an estimated number but extant for seven or eight miles along the Rio Grande; Rancho de los Placeres with 200 or 300; Tomé with 2,000; Socorro, described as a "considerable city"; Paso del Norte with 5,000 to 6,000, and Carrizal, Chihuahua, with 400 inhabitants.

There have historically been several designated "Caminos Reales de Tierra Adentro" throughout New Spain, perhaps the second most important one after the road to Santa Fe being the one that led out of Saltillo, Coahuila, to the Province of Texas.

The section of the road that runs through Mexico was nominated to the UNESCO World Heritage List in November 2001, under the cultural criteria (i) and (ii), which referred to i) "Representing a masterpiece of the creative genius of man"; and ii) "Being the manifestation of a considerable exchange of influences, during a specific period or in a specific cultural area, in the development of architecture or technology, monumental arts, urban planning or landscape design".

Criteria (iv) "Offering an eminent example of a type of building, architectural, technological or landscape, that illustrates a significant stage of human history" was added in 2010.

Five of them (Mexico City, Querétaro, Guanajuato, San Miguel de Allende and Zacatecas) had been separately recognized in the past.

The Instituto Nacional de Antropología e Historia is conducting research to find and gather evidence for additional portions and sites of the original stretches of the historical road, such as bridges, pavements, haciendas, etc.

1351-045: Templo de Nuestra Señora del Refugio in the Hacienda La Pedriceña in Los Cuatillos, Cuencamé Municipality.

By the late 16th century, Spanish exploration and colonization had advanced from Mexico City northward by the great central plateau to its ultimate goal in Santa Fe.