The city bills itself as "The Crossroads of Opportunity" because of its location at the intersection of two major Interstate highways: I-57 running from Chicago to Miner, Missouri, and I-70 running from Utah to Maryland. It also is the path of U.S. Route 45, which runs from Michigan to Alabama. Illinois Route 33 and Illinois Route 32 also run through the city. Thus, Effingham has a broad range of restaurants, lodging, and shopping facilities. Effingham is also located on U.S. Highway 40, the historic National Road, which stretches from Cumberland, Maryland to Vandalia, Illinois.
Effingham was first settled in 1814, and was known from then until 1859 as Broughton.
Some argue that Effingham is named after Thomas Howard, 3rd Earl of Effingham, who resigned his commission as general in the British army in 1775, refusing to serve in the war against the Colonies. This contention is unsubstantiated. The name is Anglo-Saxon for "Effa's house".
On April 5, 1949, St. Anthony's hospital caught fire and burned to the ground, killing 60–65 people. As a result, fire codes nationwide were improved. Due to extensive media coverage, including a "Life Magazine" cover story, donations for rebuilding the hospital came from all 48 states and several foreign countries.