Caesar and Cleopatra is a card placement board game in which players take on the roles of two great leaders. Caesar wishes for Rome to invade Egypt, while Cleopatra aims to remain independent. Players try to influence Roman officials to support their cause.

Players take turns sending their agents by playing numbered cards from 1 to 5 to influence a group of Roman officials, such as Aediles, Quaestors, Senators, Praetorians, and Censors. It is possible to send fewer agents secretly (with face-down cards) or more openly (with face-up cards).

Players can also play action cards, such as Assassins who neutralize opposing agents or Scouts who reveal hidden agents. They have the option to draw new cards either from the agent deck or the action deck, but when either deck runs out, they can no longer draw cards from it.

After each round, a card from the voting pile is revealed, and the group of officials indicated votes. The player with the most influence points next to that group wins an official on their side and removes their strongest agent from the pile.

The game ends when all officials have chosen a side. The winner is the player who has influenced the most officials, with additional points for majority in each group and for some simple, hidden objectives.