It is significant for its association with the beginning of cattle ranching in southern Arizona and northern Mexico.

The San Bernardino Valley was originally home to Southern Athabaskan Native American tribes.

The Marqués de Rubí proposed the building of the San Bernardino Garrison, which was occupied from 1775 to 1780.

The original Mexican land grant of 73,240 acres (29,640 ha), where the San Bernardino Ranch sits today, was purchased by Ignacio Perez in 1822 for 90 pesos (plus additional fees).

A historical marker commemorating their passage can now be seen at the beginning of the road leading to the front gate.

On June 8, 1854, the valley officially became part of the United States following the Gadsden Purchase from Mexico.

In 1884, John Horton Slaughter, a cowboy and lawman originally from Texas, purchased 65,000 acres (26,000 ha) from Perez's heirs for approximately $80,000.

There are ruins on the property now owned by the United States Fish and Wildlife Service where a Mormon employee of Slaughter's built a home (called the Mormon House) straddling the U.S.–Mexico border so he could keep a wife in the United States and a wife in Mexico.

He helped tame the Arizona Territory, and was known to return from searching for outlaws with only their horses and equipment.

Following the May 4, 1919 murder of Jesse Fisher by Manuel Garcia and Jose Perez, John and Viola moved to Douglas.

Today, the existing buildings at the San Bernardino Ranch have been carefully restored to their early 1900s appearance based on personal accounts and photographic records.