Prior to the coming of the first European settler to the future Pike County, French traders, hunters, and travelers passed through the native forests and prairies.

Originally Pike County began on the south junction of the Illinois and Mississippi rivers.

The Gazetteer of Illinois and Missouri, published in 1822, mentioned Chicago as "a village of Pike County" containing 12 or 15 houses and about 60 or 70 inhabitants.

McWorter had invested in land there sight unseen after purchasing the first few members of his family out of slavery.

After the railroad bypassed the town, its growth slowed and it was eventually abandoned in the 20th century.

In the early 21st century, Pike County acquired notability as a whitetail deer hunting center, especially for bowhunting.

As of the 2010 United States Census, there were 16,430 people, 6,639 households, and 4,527 families residing in the county.

Since 2000, the county has become a Republican stronghold, with Donald Trump winning it in the 2016 presidential election by a margin of 57.6 points.

The county is located in Illinois's 15th Congressional District and is currently represented by Republican Mary Miller.