In 1898, he was ordained to the office of a seventy and set apart to do missionary work in connection with his studies in Europe. He entered the University of Goettingen, Germany, and after applying himself diligently to his studies he graduated from that institution, with the degrees of A. M. Ph.D. in 1899. For part of his time in Europe, Widtsoe lived in Switzerland. The police wanted proof that he and his wife were married, and since they had neglected to bring their wedding license they got married a second time.
In 1905 Widtsoe was dismissed from the agricultural college as a result of political debates about its future and President William J. Kerr's feeling that Widtsoe was insufficiently supporting him.
For a short time he was a professor of agriculture at BYU, and is arguably the founding father of Brigham Young University's college of biology and agriculture. On BYU campus the John A. Widtsoe building is the home of the College of Biology and Agriculture. He later served as president of the University of Utah from about 1915 until his call as a member of the Quorum of the Twelve in 1921. Widtsoe was the fifth Commissioner of Church Education from 1921 to 1924 and was the seventh commissioner from 1934 to 1936.
During his time as an apostle Widtsoe taught a religion class at the University of Southern California.
Widtsoe was also part of the Genealogy committee of the church, being one of the main people behind the implementation of the Temple Index Bureau.
From 1926 until 1932 he served as president of the European Mission. While in this office, Widtsoe convinced the First Presidency to call a separate president of the British Mission, so that the European Mission president could assume his duties as the supervisor of all the missions in Europe. While president of the European mission, Widtsoe dedicated Czechoslovakia for the preaching of the gospel, and worked closely with Arthur Gaeth in starting the mission there.
Besides the Teachings of Brigham Young, Widtsoe was also the lead compiler of Gospel doctrine: selections from the sermons and writings of Joseph F. Smith, sixth president of the Church of Jesus Christ of Latter-day Saints.
Widtsoe also wrote A Rational Theology as Taught by the Church of Jesus Christ of Latter-day Saints which has been cited by later LDS authors such as J. Reuben Clark. Another book of Widtsoe's was Evidences and Reconciliations, which was actually a compilation of his Improvement Era writings, which were his answers to the questions on matters of faith he received most often. In this work Widtsoe admits that there are multiple interpretations that Latter-day Saints can hold on issues. One example is his explanation of the creation of the earth: He points out that faithful Latter-day Saints hold the six-day, six-thousand years and undefined-period interpretations of the creation. Although he gives by far the most space to the explanation of the unknown-period interpretation, he does not rigidly contest for any of these interpretations.
Widtsoe also wrote Priesthood and Church Government. His work The Message of the Doctrine and Covenants was published after his death, after having been edited by his son-in-law G. Homer Durham. Widtsoe wrote Seven Claims of the Book of Mormon: A Collection of Evidences with Franklin S. Harris, Jr.
Widtsoe wrote Joseph Smith: Seeker After Truth Prophet of God. It was published in 1951, and later reprinted by Bookcraft in 1957. It begins with an account of the first vision and goes all the way to Joseph Smith's martyrdom at Carthage. Another work by Widtsoe on Joseph Smith was Joseph Smith as a Scientist: A Contribution to Mormon Philosophy published by the Young Men's Mutual Improvement Association in 1908. In 1944, his essay "The Divine Mission of Joseph Smith" was included in Handbook of the Restoration published by Zion's Printing and Publishing Company in Independence, Missouri.
Widtsoe wrote two autobiographies. The first In the Gospel Net largely focused on his mother's conversion to the church. The second In a sunlit Land told the story of his later life, and also included explanations of his educational philosophy.
Another book by Widtsoe was Dry-Farming: A System of Agriculture for Countries Under a Low Rainfall (New York: MacMillan Company, 1920). He also served as a co-author of Dodge's Geography of Utah.
Adam S. Bennion was called to the Quorum of the Twelve after Widtsoe's death.