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.
The first print run of copies is known for having severe bugs, and had to be recalled. The original version's cover is red, while the corrected edition is white. Atelier Lise is sometimes mocked as "Atelier Freeze" (フリーズのアトリエ) due to these bugs.