Hereford, the county seat and principal town of Deaf Smith County, is on U.S. Highway 60 near the southeast corner of the county. When the Pecos and Northern Texas Railway was completed in 1899 from Amarillo to Farwell, it occasioned the growth and development of a new town, initially called Blue Water for the waters of Tierra Blanca Creek, one mile to the south. When federal postal authorities found that there was already a town in Texas with the name Blue Water, the residents renamed the settlement Hereford, after the cattle brought to the area by ranchers L. R. Bradley and G. R. (Rat) Jowell. By September 1898 W. H. Clair, Troy Womble, and C. G. Witherspoon (later a holder of various city and county offices) had established the new town's first homes and businesses. Because of the approaching railroad, in November residents of Deaf Smith County chose Hereford to replace La Plata as the county seat. The original wooden frame courthouse, transported by wagon to the new site, was used until the completion of a marble-faced structure in 1910.
By 1900 Hereford was a thriving railroad town with a population of 532. The first public school opened in 1900. Businesses included three general stores, two hotels, a restaurant, several specialty stores, Witherspoon and Gough (real estate agents and attorneys), Hereford State Bank, and wagon and feed yards. E. B. Black established his furniture store in 1901. F. L. Vanderburgh started his newspaper, the Hereford Reporter (later the Brand), at his printing office in February 1901. By 1902 five churches had been established in Hereford. Hereford College opened in September 1902 and operated for ten years.
On February 13, 1903, Hereford residents voted to incorporate; election of officers was scheduled for April 10. Ross W. Davis was elected mayor and W. G. Ross, marshal. Among the five aldermen was lawman Ira Aten. Disgruntled losers in the election, led by C. G. Witherspoon, won a referendum seeking annulment of the incorporation vote. In 1906 the town was reincorporated, however, and a Judge L. Gough was elected mayor. Under his administration the city streets were improved, and in 1910 a fire department was organized after two disastrous fires. Electric power and telephone service were also initiated during this period. In 1908 a new brick railroad depot was built, and the old depot's wooden water tank was replaced with a new well and a metal water tank. The Monday Afternoon Club, a local women's group, organized the town's first library in 1910; in 1919 it was turned over to the city, and in 1930 it became the county library. In 1910 the town's Catholic populace remodeled the old courthouse into St. Anthony's Church; later they moved this church and established a school. The Hereford Independent School District acquired the defunct Hereford College buildings and six acres of campus for a new public school in 1915.
From the town's beginning, Hereford's residents depended upon wells for their water. The plentiful groundwater supply was a major attraction to newcomers to the area. As early as 1904 Hereford was called the Windmill City because of the 400 windmills that dotted the landscape. Most of the early agriculture in the area was single-crop dry-land farming of wheat or sugar beets. In 1910, however, D. L. McDonald sank the first successful irrigation well in the Ogallala Aquifer north of town. Irrigated farming in the area became increasingly common in the 1930s and 1940s.
The city's reputation as the "town without a toothache" evidently began in 1948, when Dr. F. M. Butler attributed local dental health to natural fluoride in the area's water. Butler's discoveries were later verified by the Texas Department of Health. Over the years Hereford water came to be in worldwide demand, as did its grain products, which are widely sold in for health-food stores. During the 1920s a county hospital was opened, new schools, churches, and a city hall building were constructed, and the chamber of commerce was reorganized. The Hereford Breeders' Association was founded in 1919 and held its first annual auction the following year. The citizens of Hereford endured the dust bowl and eagerly supported the Civilian Conservation Corps, the Work Projects Administration, and other federal relief programs. In 1939 the Hereford Potato Growers Association began operation of the shed that began the area's vegetable industry. During World War II a prisoner of war camp, where mainly Italian prisoners were kept, was located south of Hereford. In 1957 Hereford's municipal airport was built northeast of town. Radio Station KPAN first went on the air in August 1948. The population increased from 2,584 in 1940 to 5,207 by 1950.
By 1985 Hereford had 385 businesses, seventeen churches, eleven schools, fourteen city parks, a municipal golf course, a shopping mall, and a modern hospital complex, complete with clinical facilities, nursing home, and training center for vocational nurses. The economy has continued to be based on the processing, storage, and shipping of cattle, grain sorghums, wheat, cotton, and a variety of irrigated vegetables. Sugar beet production expanded in 1964 with the construction of Holly Sugar Corporation's Hereford refinery. Whiteface cattle are now principally raised in feedlots rather than on the range. Arrowhead Mills, which manufactures and processing natural foods, was established in Hereford in 1960. The population continued to grow, from 7,652 in 1960 to 15,853 in 1980. Forty-three percent of the town's 1980 population was Hispanic. In 1990 the population was 14,745, and in 2000 it was 14,597. In 2016 the population was estimated at 15,730.
Hereford has a community concert series. Since 1975 the nation's largest all-girl rodeo has been held in Hereford in August. The National Cowgirl Hall of Fame and Western Heritage Center, with its magazine Sidesaddle, was founded in Hereford to pay tribute to the women of the West. It later relocated to Fort Worth, Texas, in 1994, and was renamed the National Cowgirl Museum and Hall of Fame. The Deaf Smith County Historical Museum has pioneer relics on display, and the turn-of-the-century home of rancher E. B. Black has been restored.