During the Civil War military action occurred in the area. In July 1862 near present Locust Grove a skirmish occurred when Union Col. William Weer and three hundred of his troops surprised a Confederate force of a similar number. Approximately one-third of the rebels surrendered, and the rest escaped. In July 1863 the first Cabin Creek engagement developed as Col. Stand Watie attempted to intercept a U.S. supply train traveling to Fort Gibson. Federal Col. James Williams defeated the famed Cherokee Confederate leader, who had expected reinforcements. In September 1864 Brig. Gen. Watie and Brig. Gen. Richard Gano successfully captured a Union supply train near the same location in the second Cabin Creek engagement. This led to a skirmish at Pryor Creek when Col. James Williams's Union force-marched his troops to reclaim the supply train. The Confederates escaped.

Early transportation routes helped the region develop. The East Shawnee Trail, an early cattle trail, followed the Grand River through present Mayes County. The Texas Road passed through, with two stage stops in the area. Two railroads provided services. The Missouri, Kansas and Texas Railroad was built in 1871-72, and was joined later by the Missouri, Oklahoma and Gulf Railway, whose "Golden Spike" was driven at Strang in February 1913.

In 1841 the area now comprising Mayes County became part of the Saline District of the Cherokee Nation. The creation of Mayes County began with the constitution for the proposed State of Sequoyah in August 1905. The document designated forty-eight counties. Nine of these, including Mayes, became part of the state by the Oklahoma Constitutional Convention, effective at statehood on November 16, 1907. The county name honors Cherokee Chief Samuel H. Mayes. Pryor, or Pryor Creek, named for early trader and Indian subagent Nathaniel Pryor, became the county seat.

The fertile soil of the Ozark Plateau and the climatic conditions of the Prairie Plains permit the cultivation of a variety of crops, including corn, soybeans, wheat, sorghum, and hay. The more rugged land is used for raising cattle and dairy farming. These agricultural activities played an early role in county history.

Beginning in 1941 the county's economy began to change with the creation of the Oklahoma Ordnance Works, a government-owned, DuPont-operated munitions plant located south of Pryor. Closed at the end of World War II, the facility remained empty for many years as prolonged negotiations took place to transform it into a center for industry. In 1960 the site became the Mid-America Industrial Park, and the manufacturing of paper, cement, fertilizer, and other products began to replace agriculture as the main economic activity.

Mayes County is central to the Grand River Dam Authority (GRDA), created in 1935 by the Oklahoma Legislature for flood control and hydroelectricity production. The county contains GRDA's operation and maintenance headquarters, three dams with generating facilities (the Pensacola Dam, the Robert S. Kerr Dam, and the Salina Pumped Storage Project), and the GRDA Coal-Fired Complex, a thermal-generation facility.

Interstate 44, the Will Rogers Turnpike, crosses the northwestern corner of the county. U.S. Highway 69 travels north and south in the western half, as does State Highway 82 in the eastern half. U.S. Highway 412 crosses the southern part of the county, State Highway 28 crosses the northern part, and State Highway 20 the central, all east and west.

In 1910, 13,596 people lived within the county. The population increased each decade to 21,668 in 1940. The number declined to 19,743 by 1950. From that date, the population grew to 38,369 in 2000.  One of the county's most notable citizens was Willard Stone (1916-1985), Cherokee sculptor inducted into the Oklahoma Hall of Fame in 1970. Another notable citizen, Ben Tincup (1894-1980), born in Rogers County but raised north of Pryor, was an American Indian who played major-league baseball. On June 18, 1917, he pitched a perfect game for the minor-league Little Rock Travelers. In 1982 Chouteau's Johnny Ray became the first Pittsburgh Pirate to be selected as Rookie of the Year by the National Baseball League. In 1976 Salina's Carl Belew was inducted into the Nashville Songwriters Hall of Fame for his award-winning country songs performed by Charlie Pride, Jim Reeves, Waylon Jennings, and others.

Mayes County is home to several public schools, Northeastern Technology Center, South Campus (vo-tech), and Rogers State University, Pryor Campus. There are six county properties listed in the National Register of Historic Places: the Farmers and Merchants Bank (NR 83002091) in Chouteau, the Territorial Commercial District of Chouteau (NR 83002093), the Pensacola Dam (NR 03000883), Union Mission Site (NR 71000668) near Mazie, Cabin Creek Battlefield (NR 71000669), and the Lewis Ross-Cherokee Orphan Asylum Springhouse (NR 83002092) near Salina.