On 15 January 1837 he was ordained in Bräunsdorf in the church
Zum Guten Hirten, where he was the sole pastor and taught religion classes in the local school as part of his pastoral duties. During his university time as well as during his time in the ministry, Walther experienced difficulties with the rationalistic government of the Kingdom of Saxony. He felt he could not carry out his duties as a Lutheran pastor in accordance with the confessional writings of the Lutheran Church as he had vowed at his ordination. Ferdinand and his brother Otto Hermann became acquainted with
Pastor Martin Stephan of Dresden and eventually followed Stephan's call to the liberation of orthodox Lutheranism in the United States of America.
In November 1838, Walther left his homeland on the ship
Johann Georg (one of five ships in the Stephan group to sail for America). He arrived on 5 January 1839 in New Orleans. Approximately 800 Saxon immigrants in the group settled either in St. Louis or to the south along the Mississippi River in Perry County, Missouri. Soon after the immigrants were settled in the new homeland, their leader and self proclaimed bishop, Martin Stephan, was accused of financial and sexual misconduct and was expelled from the settlement. The immigration party was deeply disturbed and unsure whether they were still a Lutheran congregation after leaving the authorities and church hierarchy in Germany behind. Walther, who was originally called to be the pastor of a dual parish in the Perry County settlements of Dresden and Johannisberg, struggled severely over the questions that the other pastors and laity were asking. In April 1841, soon after his brother Otto Herman in St. Louis had died and after a call had been extended to him by his late brother's congregation, a public disputation was held between Walther and an attorney Marbach, one of the lay leaders of the settlers, in what is known as the
Altenburg Debate. Walther convinced Marbach that they could validly consider themselves to be a church. He then accepted the call to Trinity Lutheran Church in St. Louis and served this congregation from May 1841 until his death in 1887. While still in Perry County, he was instrumental in establishing a log cabin college, which was opened in December 1839.
On 21 September 1841 Walther married the former Emilie Buenger. Six children were born to this union: Magdalene (b. 22 Nov 1842; d. 15 May 1936), Herman Christoph (b. 25 Oct 1844; died at age four), twins Constantine and Ferdinand (b. 23 February 1847; Constantine d. 21 Dec 1905, Ferdinand d. 25 May 1933), Julie (b. 27 July 1849; death date unknown) and Christian Friedrich (b. 29 June 1851; d. 29 Oct 1852). Walther's son Ferdinand was pastor at Brunswick Missouri, until his death in 1922. Both daughters became pastor's wives. Magdalene married Stephanus Keyl, who ministered in New York; Julie married J.H. Niemann and followed him to Cleveland. Constantine became a miller.