Kirtland's fragile economy collapsed in 1837. Many Mormons, including Orson Pratt, turned against Smith. But Pratt did not remain long at odds with his leader, leaving soon for a mission to New York. He reached St. Louis, where he waited out the winter after Sarah had given birth.
Following another mission, this time to England, Pratt arrived in Nauvoo, Illinois, in July 1841. During Pratt's absence, Joseph Smith had begun practicing plural marriage. One of the women he approached was Sarah, who rejected his advances. The next spring Sarah told Orson of Smith's proposals. Pratt became depressed and on 14 July disappeared; however, he was found near the Mississippi River and was persuaded to return home. In mid-August three apostles tried to convince him to sustain Smith. When he refused, they excommunicated him from the church.
Despite this, the Pratts remained at Nauvoo. When Orson later received a letter from one of Joseph Smith's detractors seeking to enlist his support, Pratt took the letter to Smith. This show of loyalty restored their friendship, and on 20 January 1843 church leaders declared Pratt's excommunication illegal, reinstated him in the church, and reappointed him as an apostle.
Concerned with protecting his people's rights, Smith sent Pratt to Washington, D.C., in March 1844. There Pratt published the Prophetic Almanac. When he learned in late July that Smith had been assassinated the previous month he returned to Illinois. In Nauvoo, the apostles defended their right to leadership of the church, worked to complete the temple, and introduced the Saints to the temple ceremonies. Meanwhile, Orson Pratt went to New York to preside over the church there and to publish The Messenger.
Returning to Nauvoo in December, Pratt found church leaders preparing to leave the city. He moved his family across the Mississippi River early the next year and then helped guide the pioneers to the Rocky Mountains. On 21 July 1847 he became the first Mormon to enter the Salt Lake Valley. The following year, Pratt returned to England, where he presided over the European Mission and edited The Latter-day Saints' Millennial Star.
In 1852 Pratt was the first to announce publicly that the church practiced plural marriage. Shortly afterwards he was sent to Washington, D.C., to publish The Seer to respond to criticisms of controversial Mormon doctrines. Pratt's theological speculations eventually made LDS Church president Brigham Young uneasy. The two men disagreed at first privately, then openly. Several times Pratt was ordered to recant his beliefs, which he did, only to resume teaching them again.
In 1856 Pratt presided over the Mormon Church in Britain again. Four years later he was called to the eastern United States. The following year, he moved to southern Utah to oversee development of a church-sponsored cotton industry. In 1864 he accepted a call to preside over the church's Central European mission.
Throughout the period from the 1850s to the 1870s when he was in Utah Pratt was a delegate to constitutional conventions and served in the territorial legislature as a member and later speaker of the house of representatives. He also prepared new editions of the Book of Mormon and other Mormon scriptures.
On 10 April 1875 the differences that divided Young and Pratt reached a climax. Young demoted Pratt from second in seniority among the apostles to fourth. Young rationalized that because Pratt had been excommunicated in 1842, he had lost his original position in the quorum even though his excommunication had been declared void.
Pratt's active involvement as a church leader waned. He died after an extended illness on 3 October 1881, two weeks after his seventieth birthday.