[2] The county was founded in 1846 and is named after Peter Wagener Grayson, an attorney general of the Republic of Texas.

The earliest known inhabitants of what is now Grayson County were Caddo Amerindian groups, including Tonkawa, Ionis, and Kichai.

[3] Trading posts were established at Preston Bend on the Red River, Warren, and Pilot Grove during 1836 and 1837.

The Great Hanging at Gainesville in nearby Cooke County in October 1862 was an attack on dissenters, men who were suspected of resisting conscription and having been Unionists.

A total of 42 men were killed in the proceedings that month, considered the largest vigilante murders in U.S. history.

The 11th Texas Cavalry Regiment captured federal forts in the Indian Territory north of the Red River.

Grayson County and much of Texas suffered economic depression in the postwar years during the Reconstruction era, based in part on difficulties in reliance on agriculture in the South, adjustments to free labor, and other problems.

The driving of cattle herds north along Preston Road provided needed income for the county during this period.

Many towns, including Denison, Van Alstyne, Howe, Whitewright, Pottsboro, and Tom Bean, were founded during this time.

In 1879, a group of settlers who had settled in North Texas both before and after statehood came together in Grayson County for political discussions.

The tornado's damage path was 400 yards (370 m) wide and 28 miles (45 km) long, and it killed 73 people and injured 200.

After rioters retrieved Hughes' body from the vault, they dragged it behind a car, hanged it, and set afire.

[9] Governor Moody sent National Guard troops to Grayson County on May 9 and more on May 10 to control the situation.

The dam's construction was completed in part by the use of labor provided by German prisoners-of-war held at Camp Howze,[10] in adjacent Cooke County during World War II.