On April 22, 1859, a meeting to organize a Lutheran congregation was held in a school building on South Fourth Street. The newly formed congregation was named the La Crosse German Evangelical Lutheran Church. The congregation became a member of the Wisconsin Synod on May 11, 1859. An old Methodist Church building was purchased and moved to a rented lot on Fifth and Jay streets. This building served as a church and school for four years. Property was purchased on the corner of Fifth and Cass streets. The old church was moved there between 1862 and 1865. In 1867, work on a new church began and was dedicated on September 26, 1869. This church was located on Fifth and Cass streets as well. A tower was built and the inside completed in 1875, and a new school building was erected in 1880.

In 1888, a congregation called the Immanuel Congregation was established on the North Side of La Crosse with the assistance of the First Evangelical Lutheran Church. The First Evangelical Lutheran Church was undergoing change in 1888 as well. Improvements were made to the interior of the church. Three bells cast in St. Louis, Missouri, in 1868 were obtained to call people to worship. Property for the new Romanesque Revival church was purchased at the corner of West and Cameron avenues. This church, located at 400 West Ave. South, was dedicated on December 17, 1905. In 1907, a parsonage was erected next to the church. The church building was damaged by fire on November 20, 1932.

In 1909, the First Lutheran School was built one block south of the church building. A kindergarten was started in 1929. A new school was built south of the old school in 1951. On September 14, 1957, a new high school, called Luther High School, opened in Onalaska. At first it consisted of individual memberships but was changed to an association of congregations in 1962 of which First Lutheran was a charter member.

Services were conducted solely in German at first. Eventually the change to conducting services in English occurred. However, until 1958 services were conducted in German and English, and thereafter solely in the English language.

In 1955, improvements were made to the church building. These included lighter aluminum shingles, repairing the main arch, replacing the front steps and sidewalks, painting and redecorating the interior, renovating the heating system and the kitchen. In 1982, additional renovation was completed on the main auditorium. This consisted of new carpeting, new paint, refinishing the pews, and eight new church doors.