In 1833 substantial numbers of German immigrant families began settling in the area, and soon they outnumbered the slave owners in the county. The German newcomers were opposed to slavery, and their sons would become Union supporters during the U.S. Civil War. Former governor and then Confederate General Sterling Price led his cavalry though the county during his Missouri raid of 1864.

Before the war Franklin County had served by steamboats that moved freight and passenger traffic on the Missouri River. Afterwards, it became a railroad transportation center. Manufacturing industries were established at the end of the Civil War and successive ones have continued.

Bias Vineyard, near the small city of Berger, is located within the Hermann American Vinticultural Area (AVA), designated in 1983. Röbller Vineyard and Winery near New haven is also in the Hermann AVA. Wineries along both sides of the Missouri River are part of the Missouri Rhineland, whose vineyards were started by German immigrants in the mid-19th century. Before Prohibition, Missouri was the second-largest wine-producing state in the nation. Everything was closed down except for limited production of wine allowed for religious purposes. The state's wine industry had to be completely rebuilt, which has been taking place since the 1960s.

In the late 19th century, Madison County became an industrial region, and in the 20th century was known first for Graniteware, and later for its steel mills, oil refineries, and other heavy industries. The county had a large working population, and the county and surrounding area was a center of strength for the Democratic Party.

Jersey County was founded on February 28, 1839, and was formed out of Greene County. The county was named for the state of New Jersey, from which many of the early settlers emigrated - which was itself named for the Channel Island of Jersey in Great Britain. The area quickly evolved into several small agricultural communities. As the area soon began to flourish, a county government was established and a courthouse was built in Jerseyville, the county seat. The cornerstone for the courthouse was laid on July 4, 1893. The Romanesque Revival style courthouse is a magnificent architectural structure of limestone quarried from the nearby town of Grafton, Illinois.