Winona is on the Mississippi River, southeast of Minneapolis-St. Paul, along I-90, and east of Rochester. Nearby towns include Preston and Red Wing, Minnesota. Lieutenant Zebulon Pike left Fort Bellefontaine on August 9, 1805 with orders to find the source of the Mississippi. On September 14, 1805, he reached the Mississippi Valley near island number 72 (on his map), which would one day be Winona, Minnesota, and recorded his impressions in his log.
Less than fifty years later, Pike's island 72 was selected by Captain Orrin Smith as a townsite on the west bank of the Mississippi River. For over twenty-five years, Smith had sailed the river between Galena, Illinois and Fort Snelling, Minnesota as owner and pilot of the river packet Nominee. In 1851 Smith learned that the treaties of Traverse des Sioux and Mendota would establish a reservation in the interior of the state, and realized that there would be a rush to develop townsites on the Minnesota side of the river. On October 15, 1851 Orrin Smith became the founder of Winona, by landing his ship's carpenter, Mr. Erwin Johnson, and two other men (Smith and Stevens) with the purpose of claiming title to the riverfront and surrounding prairie land. When the town site was surveyed and plotted by John Ball, United States deputy surveyor, it was given the name of "Montezuma", as requested by Johnson and Smith. Henry D. Huff bought an interest in the town site in 1853. With the consent of Capt. Smith, Huff erased the name of Montezuma and inserted the name of Winona on the plot, a name derived from the Dakota Indian word "We-no-nah", which translates to "first-born daughter".
Winona was settled by non-Native Americans in 1851, and the town was laid out into lots in 1852-3 with growth expanding rapidly over the years. The original settlers were old stock Yankee immigrants from New England. The population increased from 815 in December, 1855, to 3,000 in December, 1856. In 1856 German immigrants arrived as well. The Germans and the Yankees worked together planting trees and building businesses based on lumber, wheat, steamboating and railroads. Together, they were so successful that for a time Winona had more millionaires than any other city of its size in the United States. In 1860 Winona had a population of 2,456, and was third largest city in Minnesota until the late 1880s. Part of the surge in population in 1856 was the fact that land claims became legal in 1855 with the completion of land surveys and the opening of a local federal land office. It was incorporated as a city in 1857.
During the 1860s southern Minnesota was the greatest wheat producing region in the country and Winona was the main port for shipping Minnesota wheat. By 1870, Winona was the fourth largest wheat shipping port in the United States. In 1899, Bay State Milling was founded, and is still in operation today. John Laird started the first lumber mill in 1855; he later was joined by his cousins James and Matthew Norton in founding the Laird-Norton Co. The Winona sawmills reached their peak production in 1892 when they produced over 160 million board feet (380,000 m³) annually and ranked eighth in production of lumber in the upper Midwest.
A famous resident of Winona was J. R. Watkins, the man who invented the "money back guarantee" in 1868 when he started Watkins Incorporated. In the early 1900s he renamed the company the J. R. Watkins Medical Company. He died before the completion of the company's current factory and offices in 1911. Now called J. R. Watkins Incorporated, it is one of the oldest companies in the nation. The company also trades in Canada, China and as of May 2009 in the United Kingdom as Watkins UK. The company museum and factory are open for visitation and touring 6 days a week.
For a decade (1907–1917) Winona was home to pioneer American composer Carl Ruggles. Carl (Charles Sprague) Ruggles was born in East Marion, Massachusetts, on March 11, 1876. Trained as a violinist, he also studied theory and composition in Boston with Josef Claus and John Knowles Paine. (Plans to study composition with Dvorak in Prague were put off when a financial sponsor died). In 1907, he moved to Winona, where he founded, and for a decade conducted, the Winona Symphony. He also gave lessons, composed, and began painting during this time. Ruggles is often referred to together with composer Charles Ives.
In 1947 the Edstrom brothers (Harold and Everett), along with fellow musician Roger Busdicker, founded the Hal Leonard Corporation, currently the largest publisher of sheet music in the world.