[2] The area that is today known as the East Village was originally occupied by the Lenape Native Americans before later being settled by the Dutch as part of New Amsterdam.

[2]: 8  Several large farms were built in the East Village area, including that of New Netherland director-general Peter Stuyvesant.

[5] After a street grid was laid out in accordance with the Commissioners' Plan of 1811, development of rowhouses came to the East Village by the early 1830s.

[2]: 11  By the 1830s and 1840s, the East Village was known as one of New York City's wealthiest neighborhoods, though this reputation was relatively short-lived as wealthy families moved to Upper Manhattan.

[3]: 6 The lots at 106–112 Second Avenue were originally part of the Nicholas W. Stuyvesant estate before being sold to developer Thomas E. Davis between 1830 and 1835.

#106 was occupied by Ralph's daughter Harriet Mead, who was married to the son of New York City mayor James Harper.

[3]: 7 [9]: 3  At the time of the move, the WPA had been renamed the Isaac T. Hopper Home and had previously occupied a smaller location at 191 Tenth Avenue.

[10] The surrounding neighborhood went through changes in the early 20th century, as the blocks of Second Avenue around the house became known as the Yiddish Theatre District.

[11] In December 2020, the Isaac T. Hopper House narrowly avoided burning down from a blaze that engulfed the neighboring Middle Collegiate Church.

The building is slightly set back from the sidewalk and contains a small front yard behind a metal fence.

The front stoop, located half a story above ground level, is in the rightmost bay and leads to a small brownstone portico supported by Ionic columns.