It was the first Catholic cathedral built in the United States after the nation's founding, and was among the first major religious buildings constructed therein after the adoption of the U.S. Constitution.

[5] Many famous events have occurred within its walls, including the funeral Mass of Charles Carroll of Carrollton, the only Catholic signatory of the Declaration of Independence.

[5] Among other effects, these led to the founding of The Catholic University of America and efforts to evangelize African and Native Americans to Catholicism.

[9] Many people deemed holy by the Catholic Church are associated with the Basilica, including the Blessed Foundress of the Oblate Sisters of Providence, the first order for Catholic nuns of African-American descent, Mother Mary Lange;[5] Blessed Michael J. McGivney, founder of the Knights of Columbus, who was ordained a priest at the Basilica in 1877 by Archbishop James Gibbons; and St. John Neumann, who is credited with founding America's Catholic school system.

The Basilica has welcomed millions of visitors, including Pope John Paul II in 1995, Mother Teresa in 1996, and Ecumenical Patriarch Bartholomew I of Constantinople in 1997.

The cathedral is a monumental neoclassical-style building designed in conformity to a Latin cross basilica plan — a departure on Latrobe's part from previous American church architecture, but in keeping with longstanding European traditions of cathedral design.

The principal feature of the main façade is a classical Greek portico with Ionic columns arranged in double hexastyle pattern, immediately behind which rise a pair of cylindrical towers.

The light-filled interior designed by Latrobe was striking in contrast to the dark, cavernous recesses of traditional Gothic cathedrals.

The Basilica houses many precious works of art, including two heroic portraits: the first entitled Descent from the Cross by Pierre-Narcisse Guérin and the second, by Baron Charles de Steuben, depicts Louis IX of France burying his plague-stricken troops before the siege of Tunis at the beginning of the Eighth Crusade in 1270.

[13][14] Additionally, the Basilica's crypt was made accessible to the public, as well as the expansive masonry undercroft (basement) of the church.

[15] On August 23, 2011, an earthquake that jolted the East Coast from Georgia to Quebec rattled through the Basilica, sending nearly 1,000 linear feet of cracks through its ceilings and walls.

The crypt is located beneath the main altar, next to the Our Lady Seat of Wisdom Chapel, and is accessible to the public.