On her fourteenth birthday in the year 2027, a straightforward and honest middle school student named Anna Akechi is visited by a panda-like fairy, Pochitan. Guided by a mysterious pendant that appears in her room, Anna is pulled through time, slipping backwards twenty-eight years to arrive in Makoto Mirai City in 1999. Disoriented in an unfamiliar era, she quickly meets Mikuru Kobayashi, a clumsy but dedicated girl her own age who dreams of becoming a great detective and possesses a wealth of investigative knowledge.

The two girls soon witness a robbery where a treasured item is stolen. Sensing that the perpetrators are the Phantom Thieves Guild, a group of evil fairies who steal objects containing crystallized feelings called Makoto Jewels to create a world blanketed in lies, Anna and Mikuru decide they cannot ignore the trouble. Using their pendant and a Makoto Jewel, they transform into legendary warriors: Anna becomes the intuitive Cure Answer, the series' first purple-colored lead Cure, while Mikuru becomes the knowledgeable Cure Mystique. Together, they form the Star Detective Precure and establish the CUREtto Detective Agency, where they solve mysteries to protect people's smiles while searching for a way to return Anna to the year 2027. The girls are supported by Jett, a cat-like, self-proclaimed genius scientist fairy who prefers to appear in human form and serves as their tech support.

The primary antagonists are the Phantom Thieves Guild, led by the dramatic Usonoir, who acts according to prophecies from the Tome of Mirages. His generals include the master of disguise Nijee, the trendy gyaru Ageseine, and the forceful Goemon, each employing different methods to steal treasures and corrupt Makoto Jewels into monsters called Hanninda. The guild also holds a mysterious figure: Luluka Moria, a laid-back girl who works as a Phantom Thief despite also being a Pretty Cure named Cure Arcana Shadow, accompanied by her fortune-telling fox fairy Mashutan. As the series progresses, Anna and Mikuru grapple with the paradox of fighting a dark Cure while uncovering the secrets behind Luluka's allegiances.

Notable early narrative arcs focus on Anna adjusting to life as a "fish out of temporal water," discovering that her future home does not yet exist in 1999, and the fair-play whodunnit structure of each episode, which allows viewers to solve the mystery alongside the heroines. The hunt for the scattered Makoto Jewels serves as the central plot device, as collecting them is the key to restoring Pochitan's power and sending Anna back to her original timeline.