In the early and mid-1800s Sixth Avenue passed by the popular roadhouse and tavern, Old Grapevine, at the corner of 11th Street, which at the time was the northern edge of the city.

[9][10] Starting in 1926, as part of the construction of the Holland Tunnel, Sixth Avenue was widened and extended from Minetta Lane to Canal Street.

[14] According to the WPA Guide to New York City, the extension resulted in blank side walls facing the "uninspiring thoroughfare" and small leftover spaces.

[15] After the renumbering of the street's properties in 1929,[16] the Sixth Avenue extension was opened to traffic in 1930,[17] and the subway line was completed two years later.

[12] By the 1930s, a coalition of commercial establishments and building owners along Sixth Avenue campaigned to have the El removed.

[20]: 410–416 On March 10, 1957, Sixth Avenue was reconfigured to carry one-way traffic north of its intersection with Broadway in Herald Square.

[26] The intent was to honor "Pan-American ideals and principles"[27] and the nations of Central and South America, and to encourage those countries to build consulates along the avenue.

[28] It was felt at the time that the name would provide greater grandeur to a shabby street[29] and promote trade with the Western Hemisphere.

[33][34] In the mid-1970s, the city "spruced up" the street, including the addition of patterned brick crosswalks, repainting of streetlamps, and new pedestrian plazas.

[38] Manhattan Community Board 2 voted in 2014 to request a feasibility study for a protected bike lane on Sixth Avenue.

[39] The protected bike lane between 35th Street and Central Park South was reinstated in October 2020,[40][41] following advocacy from cyclists.

[55] The PATH's Uptown Hudson Tubes to New Jersey also run under Sixth Avenue (JSQ–33, HOB-33, and JSQ-33 (via HOB) trains) from 9th to 33rd Streets.