The Maryland colonial General Assembly created the Port of Baltimore at Locust Point in 1706 for the tobacco trade. The Town of Baltimore was founded on July 30, 1729, and is named after Lord Baltimore (Cecilius Calvert), who was the first Proprietary Governor of the Province of Maryland. Cecilius Calvert was a son of George Calvert, who became the First Lord Baltimore of County Cork, Ireland in 1625. Baltimore grew swiftly in the 18th century as a granary for sugar-producing colonies in the Caribbean. The profit from sugar encouraged the cultivation of cane and the importation of food.

Baltimore played a key part in events leading to and including the American Revolution. City leaders such as Jonathan Plowman Jr. moved the city to join the resistance to British taxes and merchants signed agreements to not trade with Britain. The Second Continental Congress met in the Henry Fite House from December 1776 to February 1777, effectively making the city the capitol of the United States during this period. After the war, the Town of Baltimore, nearby Jonestown, and an area known as Fells Point were incorporated as the City of Baltimore in 1796. The city remained a part of Baltimore County until 1851 when it was made an independent city.
The city was the site of the Battle of Baltimore during the War of 1812. After burning Washington, D.C., the British attacked Baltimore on the night of September 13, 1814. United States forces from Fort McHenry successfully defended the city's harbor from the British. Francis Scott Key, a Maryland lawyer, was aboard a British ship where he had been negotiating for the release of an American prisoner, Dr. William Beanes. Key witnessed the bombardment from this ship and later wrote "The Star-Spangled Banner", a poem recounting the attack. Key's poem was set to a 1780 tune by British composer John Stafford Smith, and the Star-Spangled Banner became the official National Anthem of the United States in 1931.

Following the Battle of Baltimore, the city's population grew rapidly. The construction of the Federally funded National Road (presently U.S. Route 40) and the private Baltimore and Ohio Railroad (B&O) made Baltimore a major shipping and manufacturing center by linking the city with major markets in the Midwest. A distinctive local culture started to take shape, and a unique skyline peppered with churches and monuments developed. Baltimore acquired its moniker, "The Monumental City" after an 1827 visit to Baltimore by President John Quincy Adams. At an evening function Adams gave the following toast: "Baltimore: the Monumental City- May the days of her safety be as prosperous and happy, as the days of her dangers have been trying and triumphant." Baltimore suffered one of the worst riots of the antebellum south in 1835, when bad investments led to the Baltimore bank riot.
Maryland did not secede from the Union during the American Civil War; however, when Union soldiers marched through the city at the start of the war, Confederate sympathizers attacked the troops, which led to the Baltimore riot of 1861. Four soldiers and 12 civilians were killed during the riot, which caused Union troops to occupy Baltimore. Maryland came under direct federal administration—in part, to prevent the state from seceding—until the end of the war in April 1865.
Following an economic depression known as the Panic of 1873, the Baltimore & Ohio Railroad company attempted to lower its workers' wages, leading to the Great Railroad Strike of 1877. On July 20, 1877, Maryland Governor John Lee Carroll called up the 5th and 6th Regiments of the National Guard to end the strikes, which had disrupted train service at Cumberland in western Maryland. Citizens sympathetic to the railroad workers attacked the national guard troops as they marched from their armories in Baltimore to Camden Station. Soldiers from the 6th Regiment fired on the crowd, killing 10 and wounding 25. Rioters then damaged B&O trains and burned portions of the rail station. Order was restored in the city on July 21–22 when federal troops arrived to protect railroad property and end the strike.

On February 7, 1904, the Great Baltimore Fire destroyed over 1,500 buildings in 30 hours, leaving more than 70 blocks of the downtown area burned to the ground. Damages were estimated at $150 million—in 1904 dollars. As the city rebuilt during the next two years, lessons learned from the fire led to improvements in firefighting equipment standards.
The city grew in area by annexing new suburbs from the surrounding counties, the last being in 1918, when the city acquired portions of Baltimore County and Anne Arundel County. A state constitutional amendment approved in 1948, required a special vote of the citizens in any proposed annexation area, effectively preventing any future expansion of the city's boundaries.
The relative size of the city's black population grew from 23.8% in 1950 to 46.4% in 1970. The Baltimore riot of 1968 occurred following the assassination of Martin Luther King, Jr. in Memphis, Tennessee on April 4, 1968. Coinciding with riots in other cities, public order was not restored until April 12, 1968. The Baltimore riot cost the city of Baltimore an estimated $10 million (US$ 63 million in 2011). A total of 11,000 Maryland National Guard and federal troops were ordered into the city. Lasting effects of the riot can be seen on the streets of North Avenue, Howard Street, Gay Street, and Pennsylvania Avenue where long stretches of the streets remain barren.
During the 1970s, Baltimore's downtown area known as the Inner Harbor, had been neglected and was only occupied by a collection of abandoned warehouses. Efforts to redevelop the downtown area started with the construction of the Baltimore Convention Center, which opened 1979. Harborplace, an urban retail and restaurant complex opened on the waterfront in 1980, followed by the National Aquarium in Baltimore, Maryland's largest tourist destination, and the Baltimore Museum of Industry in 1981. In 1992, the Baltimore Orioles baseball team moved from Memorial Stadium to Oriole Park at Camden Yards, located downtown near the harbor. Six years later the Baltimore Ravens football team moved into M&T Bank Stadium next to Camden Yards.
The city has 280 properties identified as historical in the National Register of Historic Places.