Originally a portion of the Northern Liberties Township, the district first gained limited autonomy from the township by an Act of Assembly on March 9, 1771. The Act provided for the appointment of persons to regulate streets, direction of buildings, etc. By March 30, 1791 a second Act enabled the inhabitants of that portion of the Northern Liberties between Vine Street and Pegg’s Run (Cohoquinoque Creek) and the middle of Fourth Street and the Delaware River to elect three commissioners to lay taxes for the purpose of lighting, watching and establishing pumps within those bounds.
During the Yellow Fever epidemics of the late eighteenth and early nineteenth centuries, the Northern Liberties district was hard hit, with many fatalities.
On March 28, 1803, the Legislature passed an act to incorporate that part of the township of the Northern Liberties lying between the west side of Sixth Street and the Delaware River and between Vine Street and Cohocksink Creek, thus creating the District of Northern Liberties. Under the Consolidation law the district ceased to exist in 1854, and become a part of Philadelphia.
Early in its history, the location just outside Philadelphia allowed the area to thrive in manufacturing, as mills, breweries, leather tanneries, paints and chemical works, tool making factories, and iron and stove foundries once lined the neighborhood. It also holds the status as a famous red-light district in the United States. Prior to annexation, the township was created as a less densely populated alternative to nearby Philadelphia. Because of this, it was later known colloquially as "Philadelphia's first suburb." However, the Southwark neighborhood claims this distinction as well.
Artisan immigrants from Germany settled in the Northern Liberties in great numbers in the 19th century. In the first decades of the 20th century, the area saw an influx of immigrants from Eastern Europe. Numbers of Slovak and Romanians left the challenges they faced in the waning years of the Austro-Hungarian Empire. Slovaks established St. Agnes Slovak Roman Catholic Church at the intersection of Fourth and Brown Street. The Romanians who settled in the area established Holy Trinity Romanian Orthodox Church at the intersection of American and Bodine Streets, where they and their descendants continue to worship.
From 1860 to 1987, the Christian Schmidt Brewing Company was located in Northern Liberties.
In 1985, the Northern Liberties Historic District was created, dedicated to preserving the Italianate architecture, Greek revival, and Federal style buildings which characterizes the area. The historic district is bounded by Brown, Boone and Galloway, Green and Wallace, and Fifth and Sixth Streets. The district encompasses 209 contributing buildings. It was added to the National Register of Historic Places in 1985. Also located in Northern Liberties and listed on the National Register of Historic Places are the Daniel Boone School, Burk Brothers and Company, Integrity Title Insurance, Trust and Safe Deposit Company, Thomas Jefferson School, Mifflin School, and St. John's Church.