Tiana is a young inhabitant of 1926 New Orleans. She has held a passion for the culinary arts since childhood, and works two jobs in order to save money and eventually open her own restaurant. Charlotte La Bouff, a débutante and childhood friend of Tiana, hires her to provide refreshments for the Mardi Gras masquerade ball being thrown by her rich father, Eli La Bouff. Eli, the perennial King of the Mardi Gras, seeks to welcome Prince Naveen of Maldonia, who has recently arrived, as an eligible suitor to his pampered daughter. Tiana is thrilled to finally have enough to purchase and renovate an old sugar mill into her restaurant.
The disinherited Prince Naveen, penniless and unskilled, is nevertheless intent on marrying a wealthy woman, rather than learning a trade. He and his valet Lawrence encounter Dr. Facilier, a voodoo witch doctor who convinces the pair that he can improve both their lives. Instead, Facilier transforms Naveen into a frog and gives Lawrence a voodoo charm, filled with Naveen's blood, which when worn transforms his appearance to that of Naveen's. Facilier intends for Lawrence, under the guise of Naveen, to marry Charlotte in order to gain access to her father’s fortune.
At the ball, Charlotte flirts with Lawrence as Tiana discovers she may lose the mill to a higher bidder. Tiana then meets Naveen, who, believing her to be a princess because of her costume, asks her to kiss him and break Facilier's curse. Tiana reluctantly agrees, in exchange for the money needed to outbid the other buyer. However, instead of Naveen turning into a human, Tiana is turned into a frog herself. A chase ensues, and Naveen and Tiana escape to a bayou.
Lawrence later proposes to Charlotte, who happily agrees, but soon the magic in Facilier's charm wears off and Lawrence reverts to his original form. Facilier tells Lawrence they need another sample of the prince's blood in order to prolong the spell, but discovers that Lawrence had foolishly released him. Facilier turns to the voodoo gods for help, with the promise that once Lawrence marries Charlotte, he will have total control over New Orleans and will be able to offer the citizens' souls as payment. The voodoo gods give Facilier shadow demons, who are then dispatched to locate Naveen.
At the bayou, Tiana and Naveen meet Louis, a trumpet-playing alligator, and Ray, a Cajun firefly. Louis and Ray offer to lead them to the good voodoo priestess Mama Odie, who they believe can undo the curse. Mama Odie tells the frogs that Naveen must kiss a true princess for them to become human, and that since Eli La Bouff is King of Mardi Gras, Charlotte is a princess, but only until the stroke of midnight, when Mardi Gras is over. Naveen soon realizes that he loves Tiana, but before he can admit his feelings, he is captured and brought to Facilier.
Before Lawrence (disguised as Naveen) and Charlotte can marry, Ray helps Naveen escape and steals the charm. Ray gives the charm to Tiana in order to hold back Facilier's minions, but is killed by Facilier. Facilier then confronts Tiana and offers to make her restaurant dream come true in exchange for the charm, but she refuses and destroys it. The angered voodoo spirits claim Facilier himself as payment for his debts and drag him into the underworld.
Tiana and Naveen reveal their love to each other and explain the situation to Charlotte, who agrees to kiss Naveen so he and Tiana can be together. Unfortunately, the clock strikes midnight before she can kiss him, but the two decide they are content to live together as frogs. After a funeral is held for Ray, Tiana and Naveen are married by Mama Odie. Because of Tiana's new status as princess, they are restored back to human form after their kiss. The couple return to New Orleans to celebrate and, with Louis' help, finally buy and open the new restaurant.