Shilkret (originally named Natan Schüldkraut) was born in New York City, United States, to parents who emigrated from Lemberg (now Lviv in Ukraine).

Shilkret was a child prodigy, touring the country with the New York Boys' Orchestra from the ages of seven to thirteen as their clarinet soloist.

The premiere recording of George Gershwin's symphonic poem An American in Paris, in 1929, was one of five conducted by Shilkret that later earned Grammy Awards.

His sponsors included Camel, Carnation, Chesterfield, Esso, Eveready, General Electric, General Motors, Hires Root Beer, Knickerbocker, Lysol, Maxwell House, Mobil Oil, Palmolive, RCA Victor, Salada tea and Smith Brothers' Cough Drops.

Between his conducting for records and for radio, virtually every musical star of the day performed under the baton of Nathaniel Shilkret.

Opera stars Rose Bampton, Lucrezia Bori, Feodor Chaliapin, Jon Crain, Richard Crooks, Miguel Fleta, Emilio de Gogorza, Amelita Galli-Curci, Mary Garden, Beniamino Gigli, Helen Jepson, Maria Jeritza, Giovanni Martinelli, Nino Martini, John McCormack, James Melton, Grace Moore, Jan Peerce, Lily Pons, Rosa Ponselle, Elisabeth Rethberg, Gladys Rice, Tito Schipa, Gladys Swarthout, John Charles Thomas, and Lawrence Tibbett were all conducted by Nathaniel Shilkret in their recordings of light-classical and popular songs.

His best-known popular composition was "The Lonesome Road", first sung by co-writer Gene Austin,[4] and later by Jules Bledsoe (dubbing Stepin Fetchit) in the final scene of the 1929 part-talkie film version of Show Boat,[4] and recorded by more than two hundred artists, including Louis Armstrong, Bing Crosby, Frank Sinatra and Paul Robeson.

His composition "Jeannine, I Dream of Lilac Time" sold almost two million copies of sheet music and was also recorded by over a hundred top artists, including Louis Armstrong, Skitch Henderson, Guy Lombardo, The London Philharmonic Orchestra, John McCormack, Mitch Miller, Hugo Montenegro, The Platters, and Lawrence Welk.

His Concerto for Trombone was premiered in 1945 by Tommy Dorsey, playing with the New York Symphony Orchestra, under the direction of Leopold Stokowski.

[1] He also received an Oscar nomination for his work scoring the film version of Maxwell Anderson's stage drama Winterset (1936).

This collaboration involved Shilkret, plus six other composers who immigrated to the United States from Europe – most of whom were Jewish – contributing one movement each: Mario Castelnuovo-Tedesco, Darius Milhaud, Arnold Schoenberg, Igor Stravinsky, Alexandre Tansman and Ernst Toch.