Prior to European settlement, the area was neutral territory for the Sac and Fox Native American tribes, who called it Shoquoquon (Shok-ko-kon), meaning Flint Hills.

[4] In 1803, President Thomas Jefferson organized two parties of explorers to map the Louisiana Purchase.

In 1805, Pike landed at the bluffs below Burlington and raised the United States Flag for the first time on what would become Iowa soil and recommended construction of a fort.

The American Fur Company of John Jacob Astor established a post in the area in 1829.

Settlement began in 1833, shortly after the Black Hawk Purchase, when Samuel (aka Simpson) White, Amzi Doolitle, and Morton M. McCarver crossed the Mississippi River from Big Island and staked claims there.

Andreas called White and Doolittle the Romulus and Remus of their settlement, referring to the mythic heroes who founded Rome, a city surrounded by hills.

[8]: 145 In the spring of 1834 they allowed John Gray, who purchased the first lot with his wife Eliza Jane, to rename the town for $50.

[11] The government used "Old Zion", the first Methodist Church in Iowa (located near what is now Third and Washington streets), to conduct its business.

[It is] beautifully elevated, situated on the west side of the Mississippi River, a place of very considerable business.

The main part of the city is situated like an amphitheater formed by the surrounding hills, beautiful buildings and private residences on the eminences around.

The river here is over 3/4 of mile wide and steam ferry boats constantly plying between this and the Illinois shore.In April 1885, economist Henry George gave a speech titled "The Crime of Poverty" at the Burlington Knights of Labor local advocating for a citizen's dividend paid for by a land value tax.

One of BNSF's main east-west lines, the Ottumwa subdivision, still crosses the Mississippi at Burlington.

After purchasing Benner Tea, Aldi opened its first store in the United States at Burlington in 1976.

Manufacturing plants are among the largest employers in the area, including companies such as American Ordnance LLC, Case Corporation, ABB (formerly General Electric), Champion Spark Plugs, Shearer's Foods and Winegard Company.

Among the oldest businesses in Burlington, the Murray factory (now Murray Turbomachinery and owned by Dresser-Rand) which has been in operation in Burlington since before 1900, the original building on Central St. and Washington St. which was divided by the local train tracks, was recently razed.

Another long-lived business is Case Corporation, which has been at its current location on Des Moines Avenue, approximately a quarter-mile from the Mississippi River, since 1937.

[27] In 2022 Ben Jacobs of The New Republic wrote that the area's economy had more problems related to late 20th century globalization compared to that of Dubuque, Iowa.

Burlington hosts the Snake Alley Criterium, one of the most physically challenging races in the Midwest.

Also in the Burlington area are the sports teams of Southeastern Community College, which have had a successful history, including three men's basketball national championships.

Beginning with the 2010–11 school year, students who had attended Oak Street Middle School (an aging building that was completed around 1907) began attending Aldo Leopold (named in honor of ecologist, and environmentalist, Aldo Leopold, a former resident of Burlington, and author of "A Sand County Almanac"), the new school building is located near the corner of Sunnyside Avenue, and Roosevelt Avenue.

Edward Stone, which opened at the start of the 2012–13 school year, is located near the corner of Lawrence Drive and Mason Road.

The middle school was named in honor of former JPL head, and Burlington educated Dr. Edward Stone.

These two new middle schools were built to accommodate more students after a third building, Horace Mann, was gutted by fire in 2005.

Burlington Community High School was constructed in 1968, and occupied the following year, with the first graduating class in June 1970.

The school district offices are located near the corner of West Avenue, and White Street, in a large mansion once owned by Railroad tycoon Charles Elliott Perkins, and is nicknamed "The White House", due to the whitewashed facade.

Burlington residents also listen to stations in nearby communities, most notably, the Quad Cities.

Initially an independent station, it became a charter FOX affiliate in 1986, but suffered from duplication from KLJB in the Quad Cities.

In 1996, the station became a full-time satellite of KLJB, marking the end of local broadcast TV in Burlington.

The older Burlington and Missouri River Railroad Passenger Station exists nearby and is also listed on the NRHP.

The Southeast Iowa Regional Airport (IATA code BRL), is located about five miles south of downtown.