The Powerpuff Hotline is a telephone that is specifically designed to call the Powerpuff Girls whenever The City of Townsville is in trouble. It's usually shown with a happy face and a red blinking nose with the following exceptions:
- In "Abracadaver", the hotline is shown with an uneasy expression when the Mayor calls the girls about the zombie fomerly known as Al Lusion attacking Townsville.
- In "Tough Love", the hotline is shown with an angry face when Ms. Keane and the students of Pokey Oaks Kindergarten throw things at the girls - no doubt a result of HIM turning the townspeople's love for the girls into hate.
- The Powerpuff Hotline somewhat bears a few resemblances to a Fisher-Price's Chatter Telephone.
- In Criss Cross Crisis, the Hotline can be connected to the giant screen from the Professor's lab and the red light can be used as a button to activate the screen. In the same episode, there is also a variant of the Hotline in a wrist watch.
- In Powerpuff Girls Z, the Hotline's role is given to Poochi, who also fulfills the role of the Talking Dog.
- In the 2016 series, the Powerpuff Hotline is now designed as a smartphone.