In 1825 a newly arrived nephew of Lewis Del Monico opened a small restaurant next to his uncle's downtown candy store. Over the years the two Swiss immigrants operated Delmonico restaurants at seven sites, venturing as far uptown as Fifth Avenue and 26th Street.

Delmonico's reputation for fine and fashionable dining grew with its movement up the island, but Uncle Lewis always favored his downtown restaurant. After he died, his nephew demolished the building and hired James Brown Lord to design this eight-story Delmonico's in 1891. The marble portal behind the front columns was reportedly brought from Pompei by the Del Monicos. Famous diners over the years were Charles Dickens, Mark Twain, and a series of American presidents.

The building has recently been restored and the upper floors turned into residences. The restaurant has re-opened as a Continental steak house, featuring some of the dishes from the original restaurant, including Lobster Newburg, a Delmonico's creation.