Lipscomb was born in Georgetown, Washington, D.C. As a young man, he entered the ministry of the Methodist Protestant church, joining the Maryland conference in 1835, and for some time was President of the Alabama conference. Compelled by ill health to retire from the ministry, he founded in 1849 the Metropolitan Institute for Young Ladies at Montgomery, Alabama. Lipscomb then served as the inaugural President (1856-1859) of the Tuskegee Female College of the Methodist Episcopal Church South in Alabama (present-day Huntingdon College located in Montgomery, Alabama).
From 1860 until his resignation in 1874, Lipscomb served as the Chancellor of the University of Georgia (UGA) in Athens. Lipscomb was the first leader of UGA to have the title Chancellor instead of President.
His tenure included a multi-year period (fall of 1863 through January 1866) during which the University was closed due to the American Civil War. Also, for the year preceding Lipscomb's Chancellorship (1859), the University had no presiding official (neither President nor Chancellor) between the time of President Church's resignation and Chancellor Lipscomb's start as the University underwent a comprehensive reorganization. His administration oversaw the construction of the library (currently the North half of the Holmes-Hunter Academic Building) in 1862 and Moore College in 1874.
Lipscomb and his first wife, Henrietta Blanche Richardson, produced many offspring that also contributed to the University. Their son, Francis Adgate Lipscomb, was a faculty member of the English department. Their grandson, Judge Thomas F. Green, served as a law professor at UGA and as a member of the Board of Regents of the University System of Georgia. Their great-grandson, Thomas F. Green Jr., also served as a faculty member of the Law School.
Lipscomb Hall, a UVA dormitory, is named in the former chancellor's honor.
After Lipscomb's academic career, he wrote Studies in the Forty Days between Christ's Resurrection and Ascension (1885) and Studies Supplementary to the Studies in the Forty Days between Christ's Resurrection and Ascension (1886). He died in 1890 in Athens and was buried in Oconee Hill Cemetery in the same city.