Many New Yorker are not acquainted with this mysterious isle, even though she is located almost in front of their noses. The 22 acres island was claimed sometime during 1611 and 1614 by Dutch explorer Adriaen Block. It was taken, along with an adjacent island to the south known as South Brother, for the Dutch West India Company. An early colonization of the Island was prevented due to the strong streaming of the East River.

NBI was uninhabited until 1885, when the city purchased the island in order to build Riverside Hospital, a hospital for people suffering from contagious diseases such as typhus, tuberculosis, yellow fever, and smallpox. Mary Mallon, also known as Typhoid Mary, was confined to the island for over two decades until she died there in 1938. The hospital closed shortly thereafter.

On June 15, 1904 over 1,000 people died either from the fire on board of the General Slocum steamship, which caught fire near the island, or from drowning before the ship beached on the island's shores. Many of the staff assisted in the rescue of some of the 321 survivors. It was the worst loss of life in US history until the September 11, 2001, terrorist attacks.

The hospital was reopened after WW2, first to house war veterans and later as a treatment for heroin addicts. In 1963, it closed its doors for good and has been left to decay ever since. The island is officially off-limits to the public, as it is a bird sanctuary for one of the area’s largest nesting colonies Night Herons and other wading shorebirds.

Over the years, various New York City mayors have explored what to do with the island. John Lindsay, for instance, proposed to sell it, and Ed Koch thought it could be converted into housing for the homeless. The city also considered using it as an extension of the jail at Rikers Island.

Most of the 25 or so original hospitals' buildings still stand, but are heavily deteriorated and in danger of collapse, and vegetation conceals and overtakes the ruined hospital buildings.