CSI: Unsolved! lets the player collect and analyze forensic evidence in five criminal cases. As a new recruit in the Las Vegas night shift, the player joins characters from the TV show like Sara Sidle, Nick Stokes and Greg Sanders in their investigations. The five cases are:
- With Sara Sidle: Pop star Jodi is found dead in her dressing room, apparently stung by a scorpion.
- With Ray Langston: The mummified remains of an unknown man are found in the desert. He appears to have drowned, but there is no water in sight.
- With Nick Stokes: A young, beautiful nurse in a posh home for the elderly is found dead. One of her rich clients had just changed his will to leave everything to her.
- With Greg Sanders: A group of CSI role-players is shocked to find one of them is killed for real.
- With Catherine Willows: A reality TV show revolving around physical challenges and endurance tests is broadcasting live when one of the two final contestants collapses on stage.
In each case, the player visits the crime scene first, collecting evidence by selecting the correct tool for the job, then returns to headquarters to process everything in a series of puzzles and minigames. David Hodges, Wendy Simms and Archie Johnson are there to assist them. The body can be inspected in the morgue with Dr. Robbins. Once enough proof has been collected to point a finger at someone, Jim Brass can be asked to bring them in for an interview. He asks the questions himself, and the player's task is to find and present any evidence that contradicts the statement. The interview will usually lead to new locations or witnesses being opened up, and after a few rounds of collecting, analyzing and interviewing, the end of the case is reached and Catherine Willows will evaluate the player's performance.