Orson Spencer entered Union College at Schenectady, New York, in 1819 and graduated with honors in 1824. He entered the teaching profession in Washington, Georgia. While teaching, he became interested in the field of law, and subsequently pursued this course of study. At about the same time, he developed an interest in religion, and shortly thereafter, in 1827, he joined the Baptist Church. This new interest led him from the study of law to the study of theology, and he entered the Theological College at Hamilton, New York, graduating in 1829 as valedictorian. He married Catharine Curtis 13 April 1830, and eight children were born to them. From 1829 to 1841 Spencer served as pastor of the Third Baptist Church in Satbrook (Deep River), Connecticut, the Second Baptist Church in Danbury, Connecticut, and the Baptist Church in Middlefield, Massachusetts.
Spencer was introduced to the Church of Jesus Christ of Latter-day Saints by his brother Daniel, who baptized him in the spring of 1841. He journeyed to Nauvoo, Illinois, where he became active in religious and civic affairs. In 1843 he served a short-term mission to New Haven, Connecticut, along with Lorin Farr. During that same year he also served in Massachusetts. Upon his return to Nauvoo, he served as an alderman.
When the Mormons were driven from Nauvoo, Spencer and his family moved with the main body of the Saints to the Iowa plains. Because of the physical trials of that experience, his wife became ill and died, leaving Orson with six children under the age of thirteen. He had received a mission call to Great Britain, and the decision was made that he should fulfill that mission. He left his children under the care of the oldest, Aurelia, with a promise that the neighbors also would look out for them. He arrived in Liverpool, England, 23 January 1827. He presided over the LDS British Mission and served as the editor of the Millennial Star for about two years. During this time he corresponded with a Reverend Mr. Crowel, and these letters were later published. His work was not completed when his term of service was up, so LDS President Brigham Young asked him to extend his mission. In the meantime, his six children, aided by others, had made their way across the plains and settled in the Salt Lake Valley, living in a dirt dugout. He was reunited with his children in 1849. While in Britain, Orson married Martha Knight, with whom he had four children. He later married Ann Dibble, Margaret Miller, Jane T. Davis, and Mary Hill.
When the University of Deseret was founded in 1850, Orson Spencer was appointed its first chancellor, a position he held until his death. He also served on the first legislative council of Utah Territory.
In 1852 Spencer was again called as a missionary--this time to Europe. He visited the Kingdom of Prussia with the intention of introducing the message of Mormonism; but the attempt failed, and he was expelled from the country. He returned to the Salt Lake Valley, and in 1853 he was called on another mission, to Cincinnati, Ohio, where he served until July 1855, at which time Apostle Erastus Snow asked him to become the editor of the St. Louis Luminary. He lived in St. Louis for a short time until he was called to go on a mission to the Cherokee Nation. On 5 August 1855 he and James McGaw began their labors among the Cherokees. They remained with the Indians until 5 September 1855, at which time they returned to St. Louis. While with the Cherokees, Spencer had become ill with chills and fever. After arriving in St. Louis, his health further deteriorated. After an illness of forty days, Orson Spencer died on 15 October 1855. He was eulogized as a man of honest heart, sterling integrity, and determination of purpose.