Middle and Late Woodland occupancy continued to about 1000CE, before the rise of the Mississippian culture along the Mississippi River and its major tributaries.

No evidence has been found that any historic Native American tribes occupied the site in the centuries before European-American settlement.

While this was part of the Illinois Country claimed by French explorers, this area was barely settled by their colonists.

It was named Fort Massac after Claude Louis d'Espinchal, Marquis de Massiac, the French Naval Minister.

After the American Revolution, initially this area was settled by people from the South, who migrated along the Ohio River.

During the Great Depression, Franklin D. Roosevelt lost the county in 1936 by a greater margin than he did in 1932, when his popularity elsewhere increased as people benefited from government programs.

In the 1964 election, following the assassination of President John F. Kennedy and during the Vietnam War, incumbent Lyndon Johnson was the first Democrat in 104 years to carry Massac County.

Locally voters opposed Barry Goldwater’s economic policies and his Deep Southern orientation.

[citation needed] Southern Evangelical Jimmy Carter marginally bettered LBJ's performance in 1976.

Bill Clinton won a larger plurality in 1992, due to a third-party challenge from Ross Perot.

[citation needed] But, since 2000 the conservative whites have shifted to the Republican Party in favoring presidential candidates.

[19] In 2016 Hillary Clinton won 23.3 percent share of the county's vote, the lowest by a Democrat since John W. Davis in his landslide 1924 loss.

Overall, state voters favored Biden, who won the election in both popular and electoral college votes.

The county did vote for Obama unanimously in the 2012 Democratic presidential primary against the anti-abortion protest candidacy of Randall Terry.