Saunders County was originally Oto Indian territory, and a large earthlodge village under Chief Itan was located here during the early historic period. Later, the Pawnee established villages in the area and in 1855 held peace conferences with General John M. Thayer.
The Ox-Bow Trail, the primary route from Nebraska City to Fort Kearny in 1845-1859, passed through this area. Pioneers first settled here in 1856 and 1857. The county's organization was approved in 1867 and the county seat located at Ashland. Wahoo was surveyed three years later and became the county seat in 1873. The origin of the name "Wahoo" is uncertain, but it is probably derived from an Oto word.
In 1883 Swedish settlers in Wahoo established a school which eventually became Luther Junior College. When Luther merged with Midland College in Fremont, the Wahoo campus was sold. In 1965 it became the site of John F. Kennedy College.
Among Wahoo's prominent native sons are artist Clarence W. Anderson, geneticist and Nobel Prize winner George Beadle, baseball player "Wahoo Sam" Crawford, composer Howard Hanson and motion picture producer Darryl F. Zanuck.