Congress designated Garfield County as O County and Enid as the county seat and government land office site prior to the opening. Initially, county business was conducted in rented space in a two-story brick structure. In 1907 the A. O. Campbell Construction Company of Oklahoma City completed an ornate, four-story courthouse, which was destroyed by fire on January 29, 1931. The present courthouse, an Art Deco design, was constructed in 1934. As part of the Works Progress Administration Federal Art Project, artist Ruth Augur painted historical murals on the courthouse walls. The Garfield County courthouse is listed in the National Register of Historic Places.

Agriculture and livestock raising have been Garfield County's principal industries. Primary crops have included wheat, corn, oats, sorghum, Kaffir corn, and alfalfa. In 1907 farmers had planted 153,430 acres in wheat, 111,083 acres in corn, 36,011 in oats, and 13,467 in Kaffir. In 1930 Garfield County reported 3,478 farms, of which 47.5 percent were operated by tenants. With 710,042 acres in farm land, the average size farm was 204.2 acres. In 1930 livestock numbered 26,140 cattle, 7,149 sheep and goats, 5,657 horses, 2,799 swine, and 2,055 mules. By 1963 Garfield County had 279,200 acres planted in wheat, 55,500 acres in barley, 29,800 acres in sorghums, and 23,600 acres in oats. At that time the livestock population stood at 71,000 cattle, 15,400 sheep, 8,500 hogs, and 2,800 milk cows. At the turn of the twenty-first century, Garfield County had 1,069 farms, with an average size of 575 acres, comprised 614,690 acres. In 2001 farmers had 305,000 acres planted in wheat and 38,000 acres in sorghum.

In addition to agriculture the county's economy has been also boosted by various industries such as oil and gas, manufacturing, flour milling, Vance Air Force Base, and Northrop Worldwide Air Services. In the 1910s and 1920s prominent oil and gas fields included the Garber-Covington, the Barnes, and the Sarah Whipple. In 1946 the Ringwood Field, west of Enid, developed. The R. E. Hoy Number One Oil Well located in Covington is listed in the National Register of Historic Places (NR 86002357). The Champlin Refining Company was headquartered in Enid. Enid has served as a principal grain storage terminal and flour milling center. Early-day businesses included the Alton broom factory and the D. C. Bass and Sons Construction Company, both located in Enid. In August 1998 Advance Foods Company announced plans to hire an additional 565 employees, making it Enid's largest nonmilitary employer.

After the 1893 land opening settlers soon established schools and other educational facilities. In September 1894 W. N. Stephenson, an itinerant teacher, established the Enid Business College. Students learned penmanship, typewriting, shorthand, telegraphy, and bookkeeping as well as spelling and arithmetic. The institution continued to operate until the mid-1970s. In September 1907 county residents and others could obtain a higher education when the Oklahoma Christian University (later Phillips University) opened. Enid club women initiated the movement to obtain a grant from the Carnegie Corporation to establish the Enid Public Library, which was dedicated in 1910.

Because Garfield County lacked major waterways, most early transportation routes followed trails. The well-known Chisholm Trail provided access across Indian Territory for cattle drives from Texas to Kansas. In 1873 a mail route was established between Wichita, Kansas, and Fort Sill, Indian Territory, that passed through the Cherokee Outlet with relay stations near present Skeleton and at Buffalo Springs, near Bison. Railroad development began four years before the land opening, and Enid became a hub as the lines crisscrossed the county. In 1889 the Chicago, Kansas and Nebraska Railway (later the Chicago, Rock Island and Pacific, CRI&P) built a line from Kansas that passed through the future counties of Grant, Garfield, Kingfisher, Canadian, and Grady. In Garfield County it connected Kremlin, Enid, Waukomis, and Bison with outside markets. In 1899 the Enid and Tonkawa Railway (later CRI&P) constructed a line between North Enid and Billings in Noble County. Passing through Breckinridge the Enid and Tonkawa Railway intersected with the Blackwell, Enid and Southwestern Railroad (later the St. Louis and San Francisco Railway) built in 1900-1901. By the early 1900s Carrier, Covington, Douglas, Drummond, Fairmont, Hillsdale, Hunter, and Lahoma had rail service. Modern motorists used U.S. Highways 60, 64, 81, and 412 and State Highways 15, 45, 74, 132, and 164.

At 1907 statehood Garfield County had 28,300 inhabitants. Numbers rose to 33,050 and 37,500 in 1910 and 1920, respectively. In 1930 and 1940 the population hovered in the mid-45,000s. During the post-World War II years, numbers increased to 52,820 and 52,975 in 1950 and 1960, respectively. Garfield County's population peaked at 62,820 in 1980. In 2000 the county had 57,813 residents.

Some of the prominent Oklahomans who have hailed from Garfield County include opera singer Leona Mitchell, Territorial Gov. Frank Frantz, and U.S. House of Reps. Page Henry Belcher and John Newbold Camp. The Covington Historical Museum as well as the Museum of the Cherokee Strip (Cherokee Strip Regional Heritage Center) and the Railroad Museum of Oklahoma in Enid offered historical displays and artifacts. Numerous historic properties were included in the National Register of Historic Places, among them the Rock Island Depot the McCristy-Knox Mansion the Enid National Guard Armory and the Enid Masonic Temple