Founded by Henry Solomon Lehr in 1871, ONU offers over 60 programs across five undergraduate and graduate colleges and is affiliated with the United Methodist Church.

Both the Great Depression and the following World War II plunged the school into low enrollment, and the possibility of closure was considered.

[6] During his visit at ONU, King famously spoke regarding the myth that many immigrant and/or ethnic groups successfully pulled themselves up by their bootstraps, whereas African Americans were incapable of doing so.

[9][10] Growth continued under DeBow Freed through the 1980s and 1990s with additions to the Taggart Law Library, Presser Hall, Dukes Memorial, Wilson Art Building, Biggs Engineering, Heterick Memorial Library, and Meyer Hall of Science, and the construction of the Freed Center for the Performing Arts and a new president's on-campus home.

Under Kendall Baker, campus additions include Dicke Hall, an expansion of the Robertson-Evans Pharmacy building, the Dial-Roberson Stadium and the Mathile Center for the Natural Sciences.

In July 2024, the administration of Ohio Northern announced the closure of Hill Building citing age and a need of extensive repairs.

[19] The ONU varsity football team defeated Mount Union College in 2005 to snap the Purple Raiders 110-game regular season winning streak.