Long before the Shredder's death, there are two teenage girls who had normal lives with their families: Penelope "Penn" Gibson, and Cassandra "Cassie" Ray. Penn's younger sister Josephine, or Jojo, is a genius and an inventor. Violetta, or Via, is Cassie's younger sister, who likes to joke around, which annoys Cassie at times.
The four girls' lives had soon change forever when one day, the Shredder kidnapped them and their families for Penn and Cassie's powers to be used in his evil intentions. Their parents bought time for their children to escape, but at the cost of their lives in the Shredder's hands.
4 years after the girls, Penn's older brother Edward and Cassie's little twin siblings Tucker and Stacy defeated the Shredder to avenge their parents sometime before four mysterious ninjas killed him, the best friends moved on with their (somewhat) normal lives. Penn and Edward work for their high school best friend April O'Neil, who knew Penn and Cassie's secret of them being human mutants. Cassie fights crime at night with her powers as a masked vigilante called the Night Mistress similar to the Nightwatcher (who is actually a certain red-masked turtle), unaware to everyone but Tucker and Stacy. Jojo keeps herself busy with building inventions as a living after she graduated from college. Via goes to night clubs to have lots of fun, sometimes inviting her sister and teenage best friends to join her, while occasionally hosting kids' birthday parties.
Although Penn is more content than her siblings and best friends, she couldn't but help wonder one thing: is there more than one mutant in New York City? What will happen when she meets one of the four mysterious ninjas, who turns out to be more than who he is? And what will happen when Cassie, as the Night Mistress, encounters the Nightwatcher and starts to find love in him?