Similar to the CSI games, NCIS is also based on a crime TV series, but instead of casting the player in a role of rookie investigator, you get to control all the major characters from the series themselves. The gameplay is a mix of exploring and forensics. While exploring and looking for evidence is done in 3rd-person perspective, all the forensics mini-games draw inspiration from the techniques used in the CSI games.

The story is told through four episodes that use same video effects and a type of humor seen in the TV series. What seems to have started as a simple bank robbery escalates into dangerous terrorist conspiracy and a nuclear threat.

Each of the characters lets the player perform different actions. While controlling "Very" Special Agent Anthony DiNozzo or Ziva David, you'll be going through the crime scenes taking photos and collecting evidence. Abby does forensics from matching bullets to taking and comparing fingerprints and more. With Dr. Mallard you perform autopsy which consists of finding the points of interest and taking snapshots which trigger doc's response. Timothy McGee hacks into computers or uses spy satellite to track fleeing suspects. And Gibbs is there to interrogate the suspects when all the necessary evidence is collected. Gibbs often calls members of his team to the deduction board which requires the player to connects pieces of evidence into a larger picture.