Cradle of Rome is a tile-matching game with a classical antiquity theme. The tiles have icons of city resources, for example piles of wood, wine barrels and coins. Matching three or more of these tiles collects them to their respective resources tab.

Three resources tabs are displayed at the top of the screen for money, wood and food. As the player progresses through the game buildings become available to build, their cost being a combination of those resources.

An amphora serves as the timer, slowly leaking water as time passes. If the player manages to finish the level before it is empty, the water remaining is added as a bonus to the resources. Otherwise, the player loses a life. Some of the board surface has marble underneath it. To complete a level, this marble has to be broken by matching the tiles over it.

Matching special tiles, like the ones with an axe, fills power-up gauges at the bottom of the screen. Once complete, these power-ups perform special actions: the axe removes single tiles, the lightning bolt destroys a random amount of them, the bomb explodes squares of nine tiles, the hourglass adds water to the amphora, etc. Once spent, their gauges must be replenished for another use. A tile with chains is immobile, stopping the flow of tiles to other parts of the board. It has to be matched once to break the chains, and again to be removed from the table.

The Nintendo DS version was ported from the PC. It has revised levels, gameplay adapted for the dual screens and an adjusted difficulty level. It also contain a new mode, Free Play, that allows the user to replay favourite boards.