The county was created by Michigan Law on April 1, 1840, from land in Sanilac County and attached to Saginaw County for administrative purposes. The Michigan Legislature passed an act on March 2, 1850, that empowered the county residents to organize governmental functions.
Tuscola County is one of five counties that are in the Thumb area region. Like the rest of the thumb, Tuscola County enjoys seasonal tourism from larger cities like Flint, Detroit and Saginaw.
According to the U.S. Census Bureau, the county has a total area of 914 square miles (2,370 km2), of which 803 square miles (2,080 km2) is land and 111 square miles (290 km2) (12%) is water.