The pilot, written by former Obama speechwriter Jon Lovett, will focus on the US President (Bill Pullman) and his dysfunctional family.
Dharma & Greg star Elfman will play the First Lady, according to TVLine.
The actress also appeared on CBS sitcom Accidentally on Purpose and will star in the final season of Damages.
Brittany Snow (Harry's Law), Josh Gad (Love and Other Drugs) and Amara Miller (The Descendants) have also been cast in 1600 Penn as the President's children.
Modern Family's Jason Winer will direct the pilot, which is in contention for NBC's 2012-13 television season.
Other comedy pilots picked up by the network include new Roseanne Barr sitcom Downwardly Mobile, Go On starring Matthew Perry and a remake of UK series Friday Night Dinner.
> Freddie Prinze Jr joins Mena Suvari in NBC sitcom