Before 1800 they made the Black Dog Trail starting east of Baxter Springs, Kansas and heading southwest to their summer hunting grounds at the Great Salt Plains in present-day Alfalfa County.

[5][6] The Osage stopped at the springs, which attracted migratory birds and varieties of wildlife, for its healing properties on their way to hunting on the plains.

Wide enough for eight men riding horses abreast, the trail was the first improved road in Kansas and Oklahoma.

As population increased and Cherokee land titles were extinguished, the legislature authorized the creation of Alfalfa County in 1907, as part of statehood.

The city of Cherokee was designated as the county seat after being chosen by voters in an election held in January 1909.

At the turn of the twenty-first century, nearly 17 percent of county residents claimed German ancestry on the census.

[10] Early railroad construction, from the Choctaw Northern line (1901), the Kansas City, Mexico and Orient (1901), the Arkansas Valley and Western (1904), and the Denver, Enid and Gulf Railroad Company (1904), contributed greatly to the county's early prosperity and caused many small towns to flourish.

Agricultural pursuits, including wheat farming and livestock raising, were major contributors to Alfalfa County's economy during the twentieth century.

Small-scale agriculture in its early years supported dozens of towns and dispersed rural communities, many of which no longer exist as a result of transportation and economic changes.

After construction of railroads, those towns bypassed by rail service, such as Carroll, Carwile, Keith, and Timberlake, did not prosper for long.

Restructuring of the railroad industry in the late 20th century resulted in abandonment of other lines, and towns such as Ingersoll and Driftwood, for example, had declining populations that made it difficult to sustain educational and city services.

Aline, Amorita, Burlington, Byron, Carmen, Cherokee, Goltry, Helena, Jet, and Lambert remained incorporated as of 2000.

Of 3,142 counties in the United States in 2014, the Institute for Health Metrics and Evaluation ranked Alfalfa County 840 in the average life expectancy at birth of male residents and 1,999 in the average life expectancy of female residents.

[25] In 2020, the Robert Wood Johnson Foundation ranked Alfalfa country as first among 77 counties in Oklahoma in "health outcomes," as measured by length and quality of life.