Play as the famous teen detective in Nancy Drew: Trail of the Twister who travels to Oklahoma and joins forces with the Canute Storm Chasers, a team trying to perfect their tornado-tracking formula and win a big-money contest. Injuries and problems with the team's equipment point to sabotage. Is a team member responsible, a competitor, or is it someone else? Nancy is just the person to find out.

As in previous games in the series, get to know each of the key people by talking to them and asking questions repeatedly. Each of them has a secret, and Nancy must discover what that is. Snoop around the town, solving puzzles and playing mini-games to reach various goals. In addition, the game touches on learning meteorology and the study of cloud formations. Nancy will come face-to-face with a monstrous tornado during the course of the game.

Trail of the Twister is a mystery adventure game and is played in first person using a point-and-click interface. There are two difficulty levels: Junior and Senior Detective.