The First Baptist Church of Waco was organized on May 31, 1851, with four charter members, who extended a call to Noah T. Byars to become their pastor on June 1. After Byars retired at the end of 1853, S. G. O'Bryan became pastor and served from 1854 to 1860. Other pastors have included Rufus C. Burleson (1862–63, 1865–67, 1870), Benajah H. Carroll (1871–99), James M. Carroll (1901–02), Joseph Martin Dawson, (1915–46), and John Wood (1981–91).
During the early years of the church, the congregation met in the Methodist meetinghouse, but in 1857 they moved into a brick building of their own at Fourth and Mary streets, where they met until 1877, when it was destroyed by fire. A program to construct a larger building was immediately launched. The new structure was finished in 1883 and served until 1907. During the pastorate of B. H. Carroll, First Baptist hosted the annual meeting of the Baptist General Convention of Texas twice. In 1906 a new building was built at Fifth and Webster streets, with a auditorium that could seat 3,000; it was still in use in the 1990s and is considered one of the most beautiful churches in Texas.
By 1854 separate Sunday afternoon services were being held for slaves who were members of the church. Black deacons were ordained, and eventually several black preachers were licensed. African Americans in the church numbered sixty-three in 1860 and seventy-six in 1864. In May 1866 letters of dismission were granted to 105 black members, who organized their own church the following month. In 1856 members of First Baptist were involved in the founding of Trinity River Male High School, later known as Waco Classical School. This institution was absorbed into Waco University when the latter was established in 1861. Waco University merged with Baylor University when Baylor was moved to Waco in 1886. In 1873 B. H. Carroll began teaching ministers in his office; their meetings led to the establishment of a Bible department at Baylor in 1893, with Carroll as chairman. Fifteen years later this department separated from the university and became Southwestern Baptist Theological Seminary, though it remained on the Baylor campus until moving to its own campus in Fort Worth in 1910. In 1899 Carroll resigned as pastor of First Baptist to devote more time to Baylor University. First Baptist was also involved in establishing in Waco in 1919 a Baptist hospital, today known as Hillcrest Baptist Medical Center. Noted members of the church have included former governor Pat Neff and Confederate generals James E. Harrison, Thomas Harrison, Joseph W. Speight, and Allison Nelson.
Throughout its existence First Baptist, Waco, has emphasized mission work. Many members have become missionaries, including the well-known couple Anne and William B. Bagby. Although First Baptist is not as prominent as it once was, it remains an influential member of the Baptist General Convention of Texas. In 1992 its members numbered 5,585 and its annual budget was almost $2 million.