In Typo 2D, you try to play your cards next to cards already on table so that you can say words that start with the letter combinations in the rows or columns. In this game's predecessor, Typo from 2004, players placed letter cards in four separate rows; in Typo 2D, players can build "words" in two directions, crossing words as in crossword puzzles. The first player to play all of his cards wins.

In each game round, all players choose one of their hand cards, then reveal them simultaneously. In alphabetical order, players place their card adjacent to a card on the table to create or extend a row or column of letters. You must then say a word that starts with the letters in this row or column. If you extend a row and a column at the same time, you must say a word for the row and a word for the column. Once five or more rows/columns consist of at least two connected cards, you may place a letter only if you extend the length of a row or column to three cards or more.

If you cannot place a letter card because you can't create a word, then you must remove all cards from the longest row or column and add half of these cards to your hand. (Set the other cards aside as a penalty pile.) If you still can't place a letter in order to create a word, you must remove another word, etc.

If you place a letter card and connect separate areas of the grid — which were separated due to someone needing to remove a word — then you discard one of your penalty cards.

Typo 2D includes icons on some cards that can be used for variants, such as a card that can replace another card or a card you must place behind an empty spot and "fill in" the empty spot by saying a word.