Cuero is at the convergence of U.S. highways 183, 77A, and 87, in central DeWitt County. It is the largest city in the county and the county seat. The first post office in DeWitt County was established in May 1846 in Daniel Boone Friar's store, four miles north of the present site; it was also called Cuero (later Old Cuero). Cuero is named after Cuero Creek, which the Spanish had called Arroyo del Cuero, or Creek of the Rawhide, in reference to the Indians' practice of killing wild cattle that got stuck in the mud of the creekbed. When the Gulf, Western Texas and Pacific Railway was extended from Indianola to San Antonio, the Cuero site was chosen as a midway stopping point in the construction of the line. Although the tracks were not completed to Cuero until January 1873, construction of business establishments and homes was begun as early as November 1872. Among the first residents were Benjamin McCulloch and Gustav Schleicher. Schleicher, who surveyed the railroad, platted the new town for his Cuero Land and Immigration Company, and Robert J. Kleberg surveyed the site in January 1873.
The city government was organized in the summer of 1873; the town was incorporated on April 23, 1875, and it replaced Clinton as county seat in 1876. Cuero grew as Clinton declined, and after the great hurricanes of 1875 and 1886 people came from Indianola. Among the significant early businesses were Otto Buchel's bank, J. R. Nagel's hardware, and H. Runge and Company, a branch of Henry Runge's Indianola-based store and bank, which was operated in Cuero by Edward Mugge, Sr. Mugge was joined by William Frobese, Sr., and Emil Reiffert, Sr., when the firm moved its operating base to Cuero after the hurricane that destroyed Indianola in 1886. These men are credited with much of Cuero's early expansion. Rudolph Kleberg began publishing the weekly Cuero Star in June 1873. Other Cuero newspapers were the Deutsche Rundschau, a German-language paper established by William T. Eichholz in 1880; Lee Chaddock's Cuero Sun, in operation by the early 1890s; the Cuero Bulletin, established in the 1880s by Samuel L. Kyle and later absorbed by the Star; the Constitution, a populist paper published in the 1890s by Fay Carothers; the Daily Hustler, issued by James C. Howerton from July to November 1894; and the Cuero Daily Record, founded in November 1894 by Howerton, H. G. Woods, and B. S. Wright. Howerton became sole owner of the Record, which absorbed the Star and Deutsche Rundschau, and is Cuero's longest running newspaper.
Professor David W. Nash opened Guadalupe Academy (also known as Nash's School or Cuero Institute), a coeducational private school, in September 1873; it operated until about 1910. The Cuero Independent School District was formed in 1892; White, Black, and Mexican-American students attended separate schools. Among the German social associations were the Order of Sons of Hermann and a turnverein (see TURNVEREIN MOVEMENT). Episcopalians organized the first Cuero congregation in 1874, and Catholics founded a church and school in 1876. Methodists built a church in 1884; Baptists organized in 1877 under Rev. John Van Epps Covey and Presbyterians in 1878. German Lutherans had organized by 1880, and their congregation grew substantially from the Indianola migrations of 1886.
Cuero prospered despite a period of lawlessness and a disastrous fire in April 1879. Citizens organized the Home Protection Club, which drilled regularly as a military unit and aided law officers when necessary (see SUTTON-TAYLOR FEUD). Shipping opportunity increased in 1886 when the San Antonio and Aransas Pass Railway connected Cuero to Houston; good dirt roads and two free iron bridges across the Guadalupe River also served the community. The town's proximity to the river provoked much discussion of Cuero's commercial future through an inland waterway that was proposed but never completed. By 1887 Cuero recorded a population of 2,500, mostly Anglos and Germans. Rudolph Kleberg recorded in his Description of the Resources of DeWitt County, Texas: The Immigrant's Handbook (1887) that Cuero had an opera house, two large schools, a fire department, and a hotel. Truck farming became an important industry, as did cotton, poultry, and livestock. The Cuero Record reported in late 1886 that the town had a railroad machine shop and a $50,000 steam-powered cotton textile factory with sixteen looms, but also noted that there was much cattle rustling in the area. By the mid-1890s Cuero also had one of the state's largest cottonseed oil mills, capable of producing eighty tons a day; there were also three large cotton gins, an ice factory, two bottling plants, a cigar factory, a tannery, a private electric company, and the first of three hospitals. The Cuero turkey industry was already shipping processed birds nationwide by 1906, though the renowned Turkey Trot parade did not begin until 1912.
Cuero had an estimated population of 3,422 in 1904 and 3,671 by the mid-1920s, at which time the town had an assessed value of $3.7 million. The power dam on the Guadalupe River, which formed part of the community's privately owned hydroelectric plant, was the largest in the state. Cuero pioneered the turkey-raising industry in south central Texas and became one of the largest poultry markets in the Southwest. The city also supported large cattle, dairy, and meat-packing industries and produced pecans, cottonseed oil and products, and feeds. Its Crescent Valley Creamery was one of the largest independent creameries in the South in 1935. Oil speculation began in 1919, although a successful well was not hit until after 1929.
The city's population rose to 5,474 by the mid-1940s and reached 7,498 in the next decade. By 1949 the broiler-chicken industry had passed turkeys as the second most important source of livestock income. The Cuero Livestock Commission records show Cuero as the largest shipper of cattle in the state in 1942 and 1943, with more than 800 carloads exported per year. The commission, established in 1940, sold $251,750 worth of stock that same year; sales jumped to $1.3 million in 1941, $3.5 million in 1942, and $4.7 million in 1943.
Cuero's population peaked about 1969 at 7,800 and had declined to 6,920 by the mid-1970s. Agribusiness still dominated the local economy, though the turkey and cotton industries had declined in significance. In the mid-1980s the population reached 7,124, and the city supported 142 businesses. The county courthouse, built in 1895–96, was restored in 1955–57. The DeWitt County Historical Museum was established in Cuero about 1974. The population in 1990 was 6,700, but dropped to 6,571 in 2000.