In 1838, many members of the Church of Jesus Christ of Latter-day Saints fled persecution in Missouri and found shelter in Quincy. Despite being vastly outnumbered by Mormon refugees, residents provided food and lodging for the displaced people. Joseph Smith then led his followers 40 miles upstream to Nauvoo, Illinois in hopes of finding a permanent home. Also in 1838, Quincy sheltered the Pottawatomie tribe as they were forcibly relocated from Indiana to Kansas.

The 1850s and 1860s brought increased prosperity to Quincy, as steamboats and railroads linked Quincy to places west, often the destination of migrants. The founding of the Chicago, Burlington and Quincy Railroad in 1855 and construction of a rail bridge in Quincy was a major drive for creating a transportation hub in the region and furthered commerce. It is during this time that the population of the city grew enormously, from a little under 7,000 in 1850 to 24,000 by 1870, helping Quincy surpass Peoria in becoming the second-largest city in the state (at that time).

In 1858,  three brothers founded one of the largest breweries in the United States in Quincy’s 9th & York area. In the early part of the 20th century, Dick Bros brewery was larger than Anheuser-Busch in St. Louis, Missouri. When the Dick brothers built their original brewery, it had an annual capacity of about 1,500 barrels of lager beer; within the next 15 years, it would produce about 70,000 barrels. Prohibition and finally the effects of WWII caused the brewery to be auctioned off under bankruptcy in 1951.

In 1860, Quincy founder and Lieutenant Governor John Wood inherited the governorship of Illinois.  At the time, he was overseeing business interests and the construction of his mansion. The Illinois legislature allowed him to stay in Quincy during his tenure, effectively making Quincy a “second” capitol for the state. His absence from the official Governor’s office in Springfield provided Abraham Lincoln a space for planning his Presidential run.

The matter of slavery was a major religious and social issue in Quincy’s early years. The Illinois city’s location, separated only by the Mississippi River from the slave state of Missouri, which was a hotbed of political controversy on the issue, made Quincy itself a hotbed of political controversy on slavery. Dr. Richard Eells, who was a staunch abolitionist, built his home in Quincy in 1835 and sheltered runaway slaves on their way to Chicago. His home became a major stop on the Underground Railroad. The divide over slavery climaxed in 1858 when Quincy hosted the sixth Senatorial debate by U.S. Senator Stephen Douglas and his challenger, Abraham Lincoln.With an estimated crowd of 12,000 in attendance, Quincy was the largest community at which Lincoln and Douglas debated.

The Civil War brought many changes and following the Reconstruction Era, Quincy was selected as the location for Illinois’ first Veteran’s Home in 1886.

Throughout the 19th Century, Quincy had grown from a backwater hamlet along the Mississippi River to become one of the state’s most important cities and ports. It was during the early decades of the 20th Century that many of the city’s historic buildings in the Downtown Quincy Historic District were constructed, including the city’s first skyscraper, the Western Catholic Union Building, in 1925.