After treaties in 1828 and 1835 future Alfalfa County lay within the vast Cherokee Outlet, owned by the Cherokee Nation but coveted by non-Indians after the Civil War. Primarily conducted by Texas cattle companies of the Cherokee Strip Live Stock Association on leased land, ranching was the principal activity from 1870 to 1890. The big outfits operating there included Miller-Pryors and Company, the British-syndicate-owned Texas Land and Cattle Company's and Cattle Ranche and Land Company's T5 Ranch (on Eagle Chief Creek near Carmen), the Eagle Chief Pool, and Drumm and Snider. The latter lease, called the U Ranch and under the direction of Maj. Andrew Drumm of Kansas City, had established a grazing operation for longhorn cattle in the Outlet perhaps as early as 1870. Headquarters were southeast of Driftwood on the Medicine Lodge and Salt Fork rivers. Cattle trails and roads crisscrossed the region from the mid-nineteenth century. One of the most significant was the Cantonment Trail, which extended southeastward from Kansas, passing the future locations of Jet, Timberlake, and Helena on its way to Canton, or Cantonment, in Blaine County.

Originally Alfalfa County was part of Woods County, created at the opening of the Cherokee Outlet in September 1893. Alfalfa County was created at 1907 statehood. The town of Cherokee, approximately in the center of the county, became the permanent seat of government through an election held in January 1909. Carmen, Ingersoll, and Jet also received votes. County officials met in rented rooms and in a schoolhouse until 1924, when a bond issue paid for a courthouse. The 1907 population stood at 16,070 but quickly grew to 18,138 by 1910, the peak year.

Alfalfa County owes its early development to railroads. Seizing the opportunity to market the huge crops of wheat produced in northern Oklahoma, three constructed a network of rail lines across Alfalfa County. The Choctaw Northern arrived first, in 1901 building north across the county through Aline, Augusta, Lambert, Ingersoll, Driftwood, and Amorita and into Kansas, with a branch that ran west from Ingersoll to Alva. The Choctaw constructed its line parallel to and in competition with the proposed Kansas City, Mexico and Orient line. The Orient constructed its tracks between 1901 and 1903, building south from Kansas through Byron, Cherokee, Yewed, Carmen, and Aline. Each railroad platted towns close to those of their competitors, in order to hamper their development. Thus Amorita and Byron, Augusta and Carmen, Ingersoll and Cherokee were in competition as wheat-shipping points and agribusiness centers. Without rail service, "inland" towns such as Carroll and Carwile, Keith and Timberlake, did not long prosper. The Arkansas Valley and Western (part of the St. Louis and San Francisco system) constructed a line from Enid, in Garfield County, west through Goltry, Helena, Carmen, Augusta and into Woods County between 1904 and 1905. The Denver, Enid and Gulf Railroad Company built from Enid northeast to Cherokee and through Ingersoll and Burlington to Kansas in 1904. The Rock Island abandoned its line south from Augusta in 1960 and from Augusta to Alva in 1984, and the Santa Fe, which had acquired the Orient in 1928, ended its north-south service circa 1991. By 2000 only the Burlington Northern Santa Fe line served the county, following the route earlier acquired by the Santa Fe from the Frisco from Goltry through Helena and Carmen.

Wheat farming, livestock raising, and state government installations anchored Alfalfa County's economy during the twentieth century. Farms, like people, became fewer in number. Like most of the agricultural counties of western Oklahoma, Alfalfa County's story is one of farm consolidation. In 1910 there were 2,533 farms, with 1,441 being in the nature of 160 acres, or a quarter section. By 1930, of 519,596 acres in 2,328 farms, only 996 were in that category, and 987 were larger, with 12 being more than 1,000 acres. By 1950, 1,647 farms existed, 936 in the up-to-1,000-acre size, and 37 of more than 1,000 acres. The 1960 census registered only 10,699 inhabitant in the county. Declining agriculture meant fewer people but higher crop production. By 2002, in 461,288 acres under cultivation, only 666 farms existed; 167 were larger than 1,000 acres. Through the twentieth and into the twenty-first century, wheat remained the largest crop, in 1961 producing 6 million bushels, third in the state, and in 2001 producing 9.95 million bushels, more than any other county. After 1950 diversified farming became important. Livestock raising increased, and by the 1960s the county was the state's second-largest producer of finished cattle.

In its early years agriculture made possible dozens of towns and dispersed rural communities, most no longer extant. Ingersoll and Driftwood, for example, were incorporated for decades but declining population made it difficult to maintain city services. Ingersoll (1901) peaked in 1910 with 253 inhabitants and Driftwood (1898) in 1930 with 71. By 1980 neither were incorporated. In 2000 Aline, Amorita, Burlington, Byron, Carmen, Cherokee, Goltry, Helena, Jet, and Lambert remained incorporated.

Some communities remained viable because they hosted government facilities and participated in oil industry activity. For example, the Woods County High School was located at Helena, rather than at the county seat, and continued briefly after the creation of Alfalfa County. The property later housed a state orphanage, a state training school for boys, and Crabtree Correctional Center, part of the state corrections system. A state fish hatchery has functioned at Byron since 1929. Wheatland Agricultural Experiment Station, southwest of Cherokee, has been maintained by Oklahoma State University and the U.S. Department of Agriculture. Great Salt Plains National Wildlife Refuge and State Park has been in operation since 1930, and tourism, particularly from bird watchers, has been an economic boon for Jet and Cherokee. Petroleum exploration and production began in Alfalfa County around the time of statehood but only became important during and after the 1930s. Drilling resumed in the late 1950s and continued in the 1970s and 1980s. By the mid-1970s the county had 2,400 producing wells.

Educational institutions proliferated. Stella Friends Academy, five miles north of Cherokee, was established in March 1894 by Quakers (the Society of Friends). It served their settlement until 1922 and eventually included high school and one year of college. Public school consolidation has been a defining feature of the county's educational history. Small rural districts combined in order to improve facilities and curriculum. In the 1960s ten districts existed, but by the 1990s only three remained independent: Timberlake (serving rural areas and Goltry, Helena, and Jet), Cherokee (serving rural areas, Cherokee, and Lambert), and Burlington (serving rural areas, Amorita, Burlington, and Byron). Young people in other parts of the county attend the schools of districts that extend into Alfalfa from adjoining other counties.

Farm consolidation reflected a drop in county population to 16,253 in 1920, 15,228 in 1930, and 14,129 just before World War II. The census registered 8,445 in 1960, 7,224 in 1970, 7,077 in 1980, and 6,416 in 1990. The populace of Alfalfa County have mixed origins. European immigrants and their children were numerous in early 1900s. Germans from Russia (ethnic Germans who immigrated to American from Russia) settled near Ingersoll, Driftwood, Cherokee, and Goltry. Many were Mennonites. Early censuses reveal a considerable number of Bohemians (also Germans) as well. At the turn of the twenty-first century nearly 17 percent of county residents claimed German ancestry.

Communities are linked by a network of roads that have taken the place of rail transport. These include State Highways 8, 11, 38, 45, and 58 and U.S. Highway 64. Notable Alfalfa County natives included Gen. William Carl Garrison, who retired in 1968 as U.S. Army Inspector General, and novelist Harold Keith, long-time University of Oklahoma sports information director. National Register of Historic Places listings include the Ingersoll Tile Elevator, and the Cleo Springs Sod House, in addition to others.