Mancuso, FBI tells the story of Nick Mancuso, a veteran of the Bureau now assigned to the Washington D.C.. He is regarded as a maverick, something that forces him sometimes to oppose elements of his own government.

The character was described by the NBC as having "a passionate love affair with the United States Constitution" and an overwhelming desire to see genuine justice rather than the mere appearance of it.

The show was based on Loggia's portrayal of the character in the NBC political miniseries "Favorite Son".