Driven by his interest in natural history, Peale began collecting (and acquiring with his own hands) specimens of birds and bones from across North America. Wealthy friends, like Thomas Jefferson, also donated pieces to his collection. The museum opened to the public in 1786. While other collections presented bones and birds as oddities of the world, Peale adopted the now familiar Linnean taxonomy of classes, orders, genera and species to organize his museum.

In the 1790s Peale began a public campaign to nationalize his museum - 56 years before the Smithsonian was dedicated. However, the young nation was embroiled with political strife and debt, the Constitution only having been ratified in 1787.

After his death, the museum was shortly cared for by his sons, but some objects were sold off to impresarios like P.T. Barnum and lost to time. The Peale Museum move to Maryland and closed in 1997 with the remaining specimens donated to the Maryland Historical Society.