Sixth Avenue is a major avenue in New York City's borough of Manhattan. Although the Avenue's official name was changed to Avenue of the Americas in 1945 by Mayor Fiorello La Guardia "Name of 6th Ave. to Be Changed To the Avenue of the Americas; Council Votes Proposal at Mayor's Request, 12 to 1, After a Debate Rages for 2 Hours --Isaacs Fears Oblivion for Historic Sites", The New York Times, September 21, 1945. p. 23 , New Yorkers seldom use this term. Calling the avenue by that name has even become a shibboleth of sorts for something a tourist in the city might say (such as mispronouncing "Houston Street"). To avoid confusion among visitors, the street is signed as both Avenue of the Americas and Sixth Avenue.

Traffic on Sixth Avenue moves uptown (northbound). At its southern end, Sixth Avenue was extended in 1926 from Bleeker Street south through Little Italy. "Ten thousand people were displaced, most of them Italian immigrants who knew no other home in America". This was done in order to ease traffic in the Holland Tunnel and to intersect Church Street diagonally a few blocks south of Canal Street.

Sixth Avenue's northern end is at 59th Street (Central Park South) where equestrian bronzes of Simón Bolívar and José Martí flank the Artists Gate traffic entrance to Central Park at Center Drive (closed to motor traffic during restricted times, such as weekends). What would be Sixth Avenue north of Central Park, above Central Park North (110th Street), is called Lenox Avenue or Malcolm X Boulevard, itself a dual-named source of confusion like its southern counterpart.

Sixth Avenue is served by the IND Sixth Avenue subway line. The PATH train to New Jersey also runs under Sixth Avenue as far as 34th Street. Formerly the elevated IRT Sixth Avenue Line ran up Sixth Avenue, darkening the street and reducing its real-estate value. After the "el" came down in stages, beginning in Greenwich Village in 1938-39, , Sixth Avenue was rebuilt during the 1960s as an all-but-uninterrupted avenue of corporate headquarters housed in glass slab towers of International Modernist style, of which the outstanding example is the CBS Building at 52nd Street, by Eero Saarinen (1965), dubbed "Black Rock" from its dark granite piers that run from base to crown with a break; it is Saarinen's only corporate tower.

Sights moving up Sixth Avenue include Greenwich Village, with the polychrome High Victorian Gothic Jefferson Market Courthouse (illustration, currently occupied by the Jefferson Market Library); the surviving stretch of grand department stores of 1880 to 1900 that runs from 14th Street to Herald Square, passing through the wholesale flower district and ending with Macy's department store; Bryant Park (40th to 42nd Streets) followed by the corporate stretch, W. R. Grace Building, with the rear of Rockefeller Center — including the Time-Life Building, Exxon Building and McGraw-Hill Building — and Radio City Music Hall. Under LaGuardia's original urbanistic proposal, Avenue of the Americas would have started at Battery Park, continuing up Greenwich Street, Trinity Place, Church Street, and then continuing up Sixth Avenue.

Recently, the National Hockey League opened a flagship retail store on Sixth Ave. between West 46th and West 47th Sts.