The region around Waynesburg is underlaid with several layers of coking coal, including the Pittsburgh No. 8 seam, the Waynesburg seam, and the Sewickley (Mapletown) seam. This area is also rich with coalbed methane, which is being developed from the underlying Marcellus Shale, the largest domestic natural gas reserve. Early in the 20th Century, four large gas compressing stations and a steam shovel factory were located in Waynesburg.
Waynesburg is named for General "Mad" Anthony Wayne, one of the top lieutenants of George Washington during the Revolutionary War (1776–81). Waynesburg also the location of the Waynesburg University and the Greene County Airport.