Number of dominoes drawn: For 2 to 4 players, each player draws 7 tiles. If 5 or more are playing, prior to the start of the game players should determine and agree upon the number of tiles each player should draw from the deck. (If 2 players, each draws 7 or 8 tiles; 3 or 4 players, draw 5 or 6 tiles.)

If there are any remaining tiles after the draw, they are discarded, not used during that hand because there will be no drawing from the boneyard.

Set domino: The player holding the highest double begins play.
After a tile has been set, play continues to the left.

How to play: The highest double is played as set. The set domino must be played on both ends and both sides, forming a 5-tile cross, before any other tile can be played. If a player is unable to match a tile from his hand with a tile in the layout, the player passes his turn to the player on his left. Each player may play only one tile per turn.

The first player to get rid of all dominoes announces "Domino!" and wins the came. If none of the players can make a play, the game ends in a block. If a game ends in a block, all the players turn the tiles in their hands faceup, count the pips on each tile, and add them together. The player with the lowest total wins the game and earns the points (1 point per pip) of all the tiles left remaining in his opponents' hands. The player who first reaches 100 points or more is the overall winner.

Set Variations: 1) highest double, and in the event no double is drawn, re-shuffle and re-draw; 2) 6-6, and in the event the 6-6 is not drawn, re-shuffle and re-draw.

Other rules: The game can be played with no spinners (which seems the most often used rule) or by using the first double as the only spinner of the game.

In most places, Maltese Cross is played to 100 points. However, there are many different variations, including to 50, 150, 200, or 101 points.