During his career, Nestico composed, arranged, or conducted albums for musicians and singers including Quincy Jones, Phil Collins, Barbra Streisand, Michael Buble, Natalie Cole, Sarah Vaughan, Toni Tennille, Frank Sinatra, and Bing Crosby.

In addition, he played trombone, in the big bands of Tommy Dorsey, Woody Herman, Gene Krupa, and Charlie Barnet.

As orchestrator, he worked on nearly seventy television programs, including Mission: Impossible,[11] Mannix, M*A*S*H,[13] Charlie's Angels,[14] and The Mod Squad.

[16] Nestico composed commercial jingles for Anheuser-Busch, Zenith, Ford Motor Company, Mattel Toys, Pittsburgh Paint, the National Guard, Dodge, Remington Bank, and Americard.

In a partnership with Billy May, Nestico was involved in the transcription, arranging, and re-recording of 630 big band songs originally recorded in the 1930s and 1940s.

[4][17] Nestico also had a career in music education, teaching at the University of Georgia from 1998 to 1999, where he taught orchestration and conducted the studio orchestra; after which he retired to Carlsbad, California, near San Diego.

He directed music programs at Los Angeles Pierce College, Woodland Hills, California, Westinghouse Memorial High School, and Wilmerding, Pennsylvania.

At the time of his death, a feature-length documentary film titled Shadow Man: The Sammy Nestico Story was in production.

[12] The Airmen of Note, the premier jazz ensemble of the USAF, sponsor an annual competition, the "Sammy Nestico Award" for composers and arrangers of big band music, named in his honor.