It is named after former United States Representative (congressman) from Massachusetts and Speaker of the United States House of Representatives Thomas P. "Tip" O'Neill Jr. (1912-1994), and located at 200 C Street Southwest in the Southwest Federal Center district, at the foot of Capitol Hill.

It is adjacent to the Center Leg Freeway of Interstate 395, which separates it from the Rayburn House Office Building.

8 to house laboratories for the Food and Drug Administration, an agency of the neighboring Health and Human Services, located across the street in the Hubert H. Humphrey Building.

The House of Representatives voted in 2012 to name the building after O'Neill, after a suggestion by then minority leader Nancy Pelosi.

The O'Neill building is shared by the House of Representatives and the Department of Health and Human Services.