Southern Maryland lower tip in 1634 was the site of the first Roman Catholic English settlement in North America, and the area later developed tobacco plantations. During the American Civil War, with a slave economy, regional sympathies were very pro-Confederate (as evidenced in the official state song lyrics), but from the beginning, large numbers of Union occupying troops and patrolling riverboats prevented the state's secession, although nighttime smuggling across the Potomac River with Virginia took place. It has traditionally been a rural and agricultural region, linked by passenger and freight steamboat routes operating until the 1930s before the building of highways and the interstate bridge on U.S. Highway 301. From 1949 to 1968 the region was known for its slot machine gambling (now illegal). Over the past few decades the region has experienced some suburban development as the Washington suburbs expand southward.

This has primarily taken place in Prince George's County and around Waldorf (a major planned community and regional shopping hub in Charles County), Lexington Park (St. Mary's County), and Prince Frederick (Calvert County) Many southern Marylanders work at Andrews Air Force Base, the U.S. Census Bureau, or at Patuxent River Naval Air Station and its related industries. Other smaller industries include a nuclear power plant and a natural gas terminal (both in Lusby), a Naval ordinance test ground (at Indian Head), an electric power plant (at Aquasco), and an oil terminal (at Piney Point). Tobacco, once a dominant crop, has greatly declined due to state government farm buyouts in the 1990s. There are Amish and Mennonite communities in St. Mary's County, and two competing groups (only formally organized in recent years) claiming to be the Piscataway native american tribe. Fishing, boating, and eating crabs are popular.