Iowa became a state in 1846.  The area where Guthrie County is located was originally part of old Keokuk County, which was comprised of approximately the western two-thirds of the Iowa. Later Keokuk County was organized with its present boundaries and Guthrie County was then part of a vast unorganized region until legislation divided the region into counties, one of which was Guthrie, in 1851. Guthrie County was named for Captain William Guthrie, formerly of Keokuk, who was the captain of the only company Iowa sent to the Mexican War. Captain Guthrie was mortally wounded in battle.

The first county seat was Panora but that would not last.  The fight for the county seat lasted for 14 years (1859-1873) between Panora and Guthrie Center.  In the end, Guthrie Center prevailed with the votes and the construction of the first brick courthouse started in 1877 for an estimated cost of $30,000.

Guthrie County was the first county in the state to comply with legislation requiring a county high school to be located in each county.  Since the courthouse was now located in Guthrie Center, the county high school was located in Panora.  The Guthrie County High School was organized in 1876 and remained a respected institute of learning until a special election vote in 1930 abolished the county school.

The first mill in the State, located west of Des Moines, was located on the Raccoon River just northwest of Panora. It was constructed by John Anderson in 1852 and would later be called the Hanyan-Beamon Mill.  Customers came to the mill from as far west as Council Bluffs, driving as far as two hundred miles, arriving as early as two o'clock in the morning, and often remained for several days.

The first railroad to be built in Guthrie County was the "narrow gauge" railroad, which was owned by Fredrick M. Hubbell of Des Moines and ran under the name of "Des Moines and Northwestern Railroad." It was the longest stretch of narrow gauge in the state of Iowa, running from Des Moines, through Panora, to Fonda, totaling 113.8 miles.  Later, the railroad became part of the Chicago, Milwaukee, St. Paul, and Pacific Railroad (CMStP&P RR). The route of the old track is now the Raccoon River Valley Recreational Trail.