Atelier Lise follows Lisette Randal, the youngest daughter of the Kingdom of Randel's royal family. King Randal was a kind, easy going king who took care of his subjects and made sure his family lived a lifestyle fit for their rank. Unfortunately, he did so by borrowing money from the Rockheim Bank, the largest financial institute on the continent. They issue his entire kingdom a forecloser notice, and plan to lay claim to the entire kingdom if the debt was not payed off by a certain date. Princess Lisette flees her home and goes to the neighboring Kingdom of Orde, hoping to discover a way to help her family and pay off the debt. She uses all her money in order to buy a house on the edge of Myslee, where she decides to become an alchemist and cash in on a growing industry. Due to the sudden popularity of alchemy, Lisette has no trouble obtaining a beginner's license and she begins to attempt to earn the money to save her kingdom.

Atelier Lise has multiple endings, which are determined by what requirements the player meets at the payment deadline. One of the endings reveal that the true one to blame for the country's economic crisis was a minister with links to the black market.

The game leaves the player with several ways to approach Lise's goal of paying back 870 004 800 cole to save her kingdom. One way is to save up the amount in in-game funds through various means, the other way is to follow the rumors of a treasure sought after by the bank and obtain the alchemy skills needed to create it. The player is also free to ignore the monetary goal and pursue other achievements within the game world.

Money can be made through fulfilling quests, defeating monsters, or selling items in the town square.

The player can use alchemy to create new items out of materials and tools. The starting tool is the traditional to the series cauldron, but it will eventually grow unpredictable and assign random traits to the finished product. Therefore specialized tools have to be obtained for ideal results and the tool used will also often determine what mini game might occur when crafting. Additionally, Supplements/Neutralizers can be used to assign traits to alchemy items.

The battle system is turn-based and allows player characters and enemies to move around on a grid. Characteristic to Atelier Lise is that skills may take several turns to charge and have limits on how often they can be used.

Notably, Atelier Lise allows players to trade items between each other.