Emily is a struggling artist that returns to her childhood home in New York, after her uncle Stanley mysteriously vanished from the city. She finds the apartment in ruins, and while searching the place for clues about her uncle's disappearance, she stumbles upon a series of keys to buildings around the town. She must collect the money hidden on each location to reform and restore Stanley's place to its former glory, and prevent its demolition by the city's authorities.
Keys to Manhattan is a hidden object game, where the main goal is to find and click on all the items listed at the bottom of the screen within a time limit, on locations around Manhattan filled with assorted paraphernalia. Each scene is presented as a static screen with three slots at bottom listing three required objects at time. The slots can alternatively display pictures of the objects instead of their names. There are twenty objects to be found on each scene, and the items light up when the cursor is hovering over them. The hint button highlights the position of one of the required objects, but takes some time to recharge after use.
The player receives a piece of furniture after completing each scene. The piece has to be rotated and put on the right place in the apartment screen that appears between each location, where the plot is developed through dialog boxes.