In 1820, the first cabin was built at Puckeshetuck, "the foot of the rapids," by Dr. Samuel Muir of Ft. Edwards, now Warsaw, Illinois, for his Sac wife.
The American Fur Company opened a trading post in 1828, which was known as "Rat Row." The log buildings of Rat Row burned in 1849.

Isaac Galland built Iowa’s first school in 1830, at a settlement called Nashville, located nine miles north of Keokuk.
In 1837, Robert E. Lee, an engineer for the government, surveyed the rapids on the Mississippi as a potential source for water power. His recommendation for improving the rapids was published that same year.
The Wisconsin Territory created Lee County in 1836, named for William Elliott Lee, a New York-based financial backer of Isaac Galland.
Isaac Galland platted the city of Keokuk in June of 1837.

Henry Christian Huiskamp moved to Keokuk in 1846 and opened what eventually became known as the Huiskamp Brothers Company, manufacturers and retailers of shoes.
The State Legislature granted Keokuk a city charter on February 23, 1847. The mayor and council were not elected until January of 1848.

On December 1, 1850, the College of Physicians and Surgeons located itself in Keokuk in a seven-story building at Third and Palean Streets. Keokuk was a medical center until 1908 when the college merged with Drake University in Des Moines.
Younker’s chain of department stores had some of their very first shops in Keokuk. Lipman Younker moved to Keokuk in 1854, and in 1856 his brothers Samuel and Marcus joined him to open a dry goods business at 82 Main Street. Besides his association with his brothers, Lipman opened up his own store at the Southeast corner of 5th and Main. He then opened the Lipman M. Younker Company, a clothing store, at 319 Walnut in Des Moines around 1880. This evolved into the Younker’s department store we know today.
On April 4, 1853, Annie Wittenmyer opened a free school for poor children at 11th and Main Streets. She was the founder of the Chatham Square Church at Seventh and Morgan Streets, which was host to such speakers as Frederick Douglass, Phineas T. Barnum, and Mark Twain. Wittenmyer began her Civil War work at the military hospital at Estes house. From there she became a Sanitary Agent for the State of Iowa, inspecting military hospitals. She was also an agent for the Keokuk Soldiers’ Aid Society, spending over one year assisting Iowa’s troops. Her own life was on the line at times, working during battles, and on riverboat hospitals transporting sick and wounded soldiers. Wittenmyer also was the founder of the diet kitchens, which used proper nutrition to nurse sick and wounded soldiers back to health. Over 100 Civil War hospitals used this diet system, and it became a permanent part of the military’s hospital system. She also met with Abraham Lincoln in the White House. Wittenmyer was appointed to the Board of Trustees of the Soldiers’ Orphans’ Home Association, and was a key figure in the founding and operating of these facilities all over Iowa. In 1868, she left Keokuk and moved East to become the first National Chaplain of the National Women’s Relief Corps, and later their president. She served as the first president of the Women’s Christian Temperance Union from 1874-1879. At the age of 73, she died at her home in Pennsylvania in 1900.
In 1857 Samuel Clemens, or Mark Twain, moved to Keokuk to help his older brother Orion publish Keokuk’s first city directory at "The Ben Franklin Book and Job Office," formerly located at 212 Main Street. His first paid articles were also printed at the shop. He left Keokuk to be a steamboat’s cub pilot on the lower Mississippi. Clemens’ mother lived in Keokuk for many years at Seventh and High Streets.

This is a drawing of what is now downtown Keokuk, possibly from the late 1850's

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