Ernest Leroy Wilkinson was born in Ogden, Utah, on May 4, 1899. He grew up on the outskirts of the city, one of seven children. Ernest enrolled in Weber Academy, and he was characterized by his hardworking nature. He served in the Student Army Training Corps in 1918. He then attended Brigham Young University (BYU), where he was very active in student activities and politics. He graduated with a Bachelor of Arts degree in 1921. He married Alice Valera Ludlow on August 15, 1923; they would go on to have three sons (Ernest L., David L., and Douglas D. Wilkinson) and two daughters (Alice Anderson and Marian Jensen). Ernest and Alice moved to Washington, D.C. where he attended George Washington University while teaching at a business high school. He graduated summa cum laude with a Bachelor of Laws in 1926. He thereafter attended Harvard University. He graduated in 1927 with a Doctor of Juridical Science (S.J.D.). He founded a law firm with Walter G. Moyle in Washington, D.C. in 1935; this partnership was dissolved in 1940. In 1935, he served as a lawyer for the Ute Indian tribes as they successfully gained compensation for land. Around 1950, he founded the law firm of Wilkinson, Boyden & Cragun with John S. Boyden, John W. Cragun, and his brother, Glen A. Wilkinson. The firm was reorganized as Wilkinson, Boyden, Cragun & Barker in 1953, Wilkinson, Cragun, Barker & Hawkins sometime between 1954 and 1956, and finally as Wilkinson, Cragun & Barker in 1957; the firm continued to be called Wilkinson, Cragun & Barker until after Ernest L. Wilkinson's death in 1978, with Glen A. Wilkinson, John W. Cragun, and Robert W. Barker as partners with Ernest L. Wilkinson.

In addition to his work as president of BYU, Wilkinson served in various organizations, including serving on the board of directors for the Deseret News, KSL, Beneficial Life Insurance Company, and the National Right to Work Committee. He received recognition from multiple organizations for his life of service, including three honorary degrees: a Doctor of Laws (LL.D.) from BYU in 1957, a Doctor of Public Service (D.P.S.) from Fort Lauderdale University in 1970, and another Doctor of Laws (LL.D.) from Grove City College in 1971.

Upon being named president of BYU in 1951, Wilkinson proceeded to aggressively expand the university. His presidency was marked by controversies surrounding his handling of issues of race, LGBTQ rights, and women’s rights and feminism. Wilkinson was also accused of political bias and of starting a ring of students to spy on professors and other students. Under his presidency, BYU grew to the largest private university in the United States. The intellectual standards of BYU also increased dramatically. In 1964, he resigned from BYU to campaign as the Republican candidate to represent Utah in the United States Senate. His campaign was unsuccessful, and in 1965 he returned to the presidency of BYU. He was replaced by Dallin H. Oaks in 1971.

Ernest L. Wilkinson passed away April 6, 1978, in Salt Lake City, Utah.