The Port first drew attention for its ships in 1670 and was designated a port of entry by the General Assembly in 1706. Fells Point, the deepest part of the harbor, was home to numerous shipbuilders, and later would gain renown for its Baltimore clippers, as well as the Continental Navy. Its natural depth made Fells Point a center for trade and shipping, and, in 1773, it was incorporated into Baltimore City.

As Baltimore grew into a city during the Revolutionary War, the Port of Baltimore became a center for the trade with the West Indies that supported the war effort. Marylanders recognized the need to protect the Port. An earthwork fort, known as Fort Whetstone, was erected in 1776 on Whetstone Point, the narrow peninsula between branches of the Patapsco River. Wardens of the Port were authorized in 1783 to oversee construction of wharves, clear waterways, and collect duties from vessels entering and clearing the Port (Chapter 24, Acts of 1783).

Trade with China commenced in 1785 as John O'Donnell brought in goods to that part of the City called Canton, just east of Fells Point, and, during the nineteenth century, Baltimore clipper ships sped around the world and developed a particularly lucrative trade with South America.

To protect the Port, Fort McHenry replaced the Whetstone earthworks in 1794. Near the old fort, masonry stood in place of earthen walls, and more cannons were added, creating an upper and lower battery. The need for this more defensive structure was proven at the Battle of North Point during the War of 1812.

Although Baltimore was a port long before it was a city, the State delayed its role in port development until 1827. Then, the Governor began annually to appoint State wharfingers who took charge of State-owned or leased docks, particularly those adjacent to the State Tobacco Warehouse.

With the Baltimore and Ohio Railroad connecting to Port warehouses at Locust Point in 1845, Baltimore became the commercial gateway to an expanding nation. As supply and demand grew for imported goods to Baltimore, ship production and design increased.

Over time, the Port changed dramatically, most noticeably in its depth and width. In 1830 the U.S. Army Corps of Engineers surveyed Baltimore Harbor, establishing the central lane depth at 17 feet. Though dredging had been conducted earlier, the River and Harbor Act of 1852 first authorized dredging to obtain specific dimensions. The Act created a channel, some 22 feet deep and 150 feet wide, from Fort McHenry to Swan Point. To decrease sediment accumulations and reduce the need for dredging, in 1869 Brewerton Channel was created. Also 22 feet in depth, this new channel was 200 feet in width. Over the years, new channels have been added, deepened, and widened. Today, the main channel reaches 50 feet down and 800 feet across. Brewerton Channel was widened further in 2001. Currently, it is 35 feet deep and 600 feet wide. In 2012, the Seagirt Terminal berth also was deepened to 50 feet.