At the time of the formation of the General Conference of Seventh-day Adventists in 1863, Smith was elected as the first secretary.

As a theologian in residence at church headquarters he regularly taught Bible classes, and ministerial workshops, and chaired the college board.

As the author of numerous books, Smith carved some of the first woodcut illustrations published by early Sabbatarian Adventists.

His older sister Annie R. Smith was an early Seventh-day Adventist poet and hymnist.

His main contribution to Adventist theology was a commentary on the prophetic Biblical books of Daniel and the Revelation, but he also wrote extensively on conditional immortality and other topics.

While SDA co-founder Ellen White wrote many things saying how she "loved Brother Smith next to my own husband and children because he has had a part in the work for so many years.

"[5] In 1883 he was one member of five people who was appointed the task of removing the grammatical imperfections in the writings of Ellen White.

[6] Along with General Conference president, Elder Butler, Uriah Smith was one of the two top figures in the Seventh-day Adventist Church to reject the message of Righteousness by Faith, brought by Jones and Waggoner to the General Conference session Minneapolis in 1888.