The town name honors the Wyandotte tribe, removed to the area in 1867.
In 1869, the Society of Friends (Quakers) established a mission in the vicinity. The Wyandotte Tribal Council donated land for the Quakers, with the approval of the commissioner of Indian Affairs, to operate a boarding school for Seneca, Wyandotte, and Shawnee children.
In 1871, campus construction began, with classes beginning in 1872.
It has had several names, including Wyandotte Mission, Seneca Indian School, Seneca, Shawnee, and Wyandotte Industrial Boarding School, and Seneca Boarding School.
It closed in 1980. After the October 1900 death of Quapaw Agency head Edward Goldberg.
In 1876, the Prairie City post office (established in 1872) moved three miles east to present Wyandotte and changed its name to Grand River.
After the Wyandotte tribe finished the allotment process, Grand River changed its designation to Wyandotte in 1894.
The Quapaw Indian Agent had claimed that Wyandotte consisted of a post office and a few houses.
The town was platted in 1895, with the survey approved by the U.S. Northern District Court of Indian Territory in 1896.
By 1900, the population stood at 224, and a 1901 Indian Territory gazetteer noted that the incorporated town had six general stores, two hotels, two liveries, a blacksmith, a flour mill, a millinery, a meat market, and a drug store.
In 1940, the Grand River Dam Authority completed the Pensacola Dam, creating Lake O' the Cherokees, known as Grand Lake.
The population has slowly increased, reaching 336 in 1980 and 366 in 1990.
In 1909, the first public school opened, and in 1921 it became Ottawa County's Consolidated School District Number One.
In 2000, Wyandotte's school district enrolled 765 in kindergarten through the twelfth grade
