The fifth president of Eastern, William Francis O'Donnell, was born May 1, 1890, in Burnet, Texas. After attending elementary and secondary school in his native state, O'Donnell matriculated to Transylvania University where in 1912 he earned the Bachelor of Arts degree. Service as Principal (1912-1913) and Superintendent (1913-1926) of the Carrollton, Kentucky public schools followed. In 1926 O'Donnell became Superintendent the Richmond Public Schools. While in that capacity, O'Donnell received the Master of Arts Degree from Teachers College, Columbia University.

In April of 1941, the Board of Regents chose him to succeed Herman L. Donovan as President of Eastern Kentucky State Teachers College July 1, 1941. America's entry into World War II followed closely O'Donnell's assumption of his post. Attendance at Eastern plummeted as Kentucky's sons and daughters rushed to volunteer their services to their country. The establishment of Army training units on the campus helped to ease the shock. After the end of the war, enrollment began a steady increase, helped by the G.I. Bill of Rights which enabled many veterans to obtain higher educations. A change in name to Eastern Kentucky State College and permission to grant degrees in fields other than teaching symbolized the maturation of Eastern under O'Donnell's leadership. In addition, the 1950's saw the beginnings of a building program which culminated in the great physical growth of the college in the 1960's.

On June 30, 1960, O'Donnell retired as President of Eastern. Continuing to reside in Richmond, the former President and his wife were familiar figures at campus events until their deaths three months apart in 1974.