[3] The northern sections of the avenue would be graded and cut through at various intervals throughout the 19th century as the northward development of the island demanded.

[20][21][22][23] The base of Windsor Tower along First Avenue had been previously occupied by larger retail stores, including an auto showroom, when the sidewalk did not run through the building.

[36] From 2019 to 2023, a temporary bike lane was established in the tunnel on First Avenue adjacent to the United Nations headquarters to provide a detour for bicyclists when the street level bike lane was closed as a security measure during the general debate of the United Nations General Assembly.

[37] A permanent bike lane in the tunnel was planned for implementation prior to the start of the United Nations General Assembly's 79th session in September 2024.

Starting in the south at Houston Street, First Avenue passes through the East Village, once a predominantly German and Jewish neighborhood, now a gentrified area populated mostly by hipsters and yuppies.

[40] The New York Veterans Affairs Medical Center, the Bellevue Hospital, and NYU Langone Health fill the blocks from there to 34th Street.

Crossing under the Queensboro Bridge through a 90-foot-wide (27 m) Guastavino tile arch, First Avenue enters the Upper East Side and runs through a number of residential areas.

Another concentration of hospitals is located in the area between First Avenue and the FDR Drive from 62nd to 72nd streets, which is also locally referred to as "Bedpan Alley.

First Avenue in Italian Harlem was the site of a major open-air pushcart market in the late 19th and early 20th centuries.

[46] Other bus routes include the following:[46] The New York City Subway's BMT Canarsie Line has a station at 14th Street.