In 1868, Penrose became the president of the church's London Conference (equivalent of a modern LDS district).

Penrose wrote a set of mission tracts entitled "Rays of Living Light" which were widely used until about the middle of the 20th-century.

The cabin the Penrose family lived at in Farmington is now a museum of the Daughters of the Utah Pioneers.

In 1864, Ezra T. Benson convinced Penrose to move to Logan, Utah, where he continued to work as a farmer and school teacher.

While on this mission he published several songs and hymns, including "Beautiful Zion for Me", which was written on the occasion of Brigham Young, Jr. leaving for Utah.

In 1877, Penrose became the assistant editor of the LDS Church-owned Deseret News in Salt Lake City, working under George Q. Cannon.

In 1884 Penrose was called a counselor to Angus M. Cannon in the presidency of the Salt Lake Stake.

Penrose, along with George Reynolds and John R. Winder, edited the 1890 Manifesto and prepared it for publication after being given the initial text by Wilford Woodruff.

Penrose preached in all the lands of the United Kingdom, as well as in Germany, Switzerland, Sweden and Denmark while on this mission.

[13] In late 1889 Penrose was pardoned by Cleveland for polygamy, and shortly after went to prison for contempt of court for refusing to testify against other polygamists.

James E. Talmage filled the vacancy in the Quorum of the Twelve caused by Penrose's being called into the First Presidency.

After Joseph F. Smith's death in 1918, Penrose was retained as Second Counselor by new church president Heber J.

On March 10, 1921, Penrose became First Counselor in the First Presidency, following the death of Anthon H. Lund, who had died eight days earlier.

Penrose served in the First Presidency until his death in Salt Lake City from chronic prostatitis.

[16] In the Improvement Era on the occasion of his death George H. Brimhall published a poem praising Penrose for his works of hymns.

Penrose's "Up, Awake, Ye Defenders of Zion"—originally a militant hymn containing references to trials of Latter-day Saints in the central United States and the threatening United States government (ironically set to the melody for "Columbia, Gem of the Ocean")—became an anthem for Latter-day Saints during the difficulties preceding and during the Utah War of 1857–58.