Three Sisters is named after an indigenous agricultural technique still widely used today in which three different crops — in this case, pumpkins, corn, and beans — are planted close together. Corn provides a lattice for beans to climb; the beans bring nitrogen from the air into the soil; and the squash provides a natural ground cover to reduce weeds and keep pests away.

In the game, you have your own player sheet. On your sheet, there are interconnected tracks. Draft dice to advance on these tracks and gain points, advantages, and/or bonuses. After eight rounds, you score points for harvested crops, perennials, the apiary, fruit, and some shed items. Whoever has the most points wins.

Three Sisters has a solo mode in which you try to top your own score against an "opponent" that drafts dice and blocks areas of your sheet.