Before his acting career, he belonged to the R&B singing group The Three Riffs, which was active from the late 1940s and performed at upscale supper clubs in New York City.

In the 1982 film, The Verdict, Seneca played Dr. Thompson, a small-town women's hospital physician brought in by attorney Frank Galvin (Paul Newman) to support his belief that two famous doctors' incompetence left his client alive but in a coma.

Arguably his most well-known roles are that of bluesman Willie Brown in Crossroads (1986) and Dr. Meddows in The Blob (1988), the evil head of a government team sent to contain the title creature.

[citation needed] Seneca also made multiple appearances on The Cosby Show as Hillman President Dr. Zachariah J. Hanes.

He also played Alvin Newcastle, a man suffering from Alzheimer's disease, on an episode of The Golden Girls titled "Old Friends".