After many failed attempts from his rodent subjects to find food, the Rat King learns of an abandoned canister of mutagen lost in the sewers and claims it for himself. Then, he kidnaps Irma and Vernon and uses the mutagen to transform them into his mutant slaves, for the sole purpose of raiding food warehouses. It is later discovered that the mutations are unstable and can only be active if the Rat King plays his hypnotic flute.
When Michelangelo decides to put one of Donatello's inventions on max power for his own entertainment, he ends in a--quite literally--little problem. April and Vernon get caught in the shrinking ray while getting footage of a military ship and join Michelangelo on his wild adventure.
Dr. Polidorius, a mad scientist plotting to mutate all humanity into aquatic-beings, creates Ray (not the similarly-named Mighty Mutanimals character), who possesses several abilities of different marine species. Ray kidnaps April O'Neil, and Polidorius mutates her into a fish-woman to be Ray's mate.
Shredder has a plan to destroy the Turtles, but with the Technodrome's portal out of commission, he is unable to challenge them on Earth, so he uses the Dimensional Teleporter to bring his enemies to Dimension X.
Donatello earns his degree from Sopho University, but discovers that he has been mistaken for a girl, so he asks Irma to masquerade as him. Meanwhile, the real Donatello discovers a plot by Professor Philo Sopho to destroy the Earth.
While trying to contact the Turtle Nebula, Donatello meets an intelligent lizard alien named Algernon ("Algae" for short), who must help him and the other Turtles rescue April from a greedy man named Hostile Hiram Grelch.
While helping April investigate a report of giant monsters attacking a superstitious farming village, Leonardo is mistaken for an alien from another planet. The lone Turtle must avoid being hunted down into extinction while also trying to rescue April from a mad scientist
The Turtles travel to a FairyTale Dimension in an attempt to save the city from Shredder's Docilizer, while also making friends with a local citizen of that dimension, Hokum Hare (based on the Hare character from "The Tortoise and the Hare").
Set up as a follow-up episode, Hokum Hare and the Turtles hitch a ride on a time-traveling train to 2036, where they discover that Shredder has plans for the future New York City. Ultimately, the Turtles of both the past and the future must team up to thwart Shredder before his actions cause all of time to be destroyed.
A family secret is revealed when Lieutenant Kazou Saki arrives from Japan to arrest his brother Oroku Saki, who turns out to be the Turtles' greatest enemy. Shredder and Krang send the Technodrome from Dimension X to Earth, but Donatello re-programs it to crash in the Arctic.
A delivery boy accidentally falls into Krang's new unstable Mutagen and becomes able to transform into anyone he chooses. Shredder tricks him into helping him launch the Mutagen into space and mutate the world, but this "Mutagen Man" has other ideas.
Donatello has tricked out the Turtle Van, but while taking it for a test drive, it's stolen from him by a family of robbing hillbillies. Can Donatello get the Van back in time before his brothers find out?
Tired of fixing everything in the lair, Donatello decides to clone himself so he can work on his other inventions. However, Donatello's clone turns against him and joins the Rat King in an attempt to conquer the city with a rat infestation.
Bebop and Rocksteady botch another mutagen experiment, resulting in a giant ice creature who Bebop dubs "Frosty", and Shredder uses this monster to freeze New York solid, preoccupying the Turtles long enough for him to steal thermal explosives needed to melt the Technodrome free from the ice.
A mad professor named Mindbender creates a law-enforcement robot named "LEX" to clean up crime in New York, but LEX ultimately starts arresting numerous innocent people for the smallest infraction. With the other Turtles unreachable, Leonardo must discover his own innate skills to stop this rogue robot before he and Mindbender declare themselves dictators of the city.
Zach, the Turtles' young friend, is put into military camp by his parents after making numerous false reports of aliens, only to find two real aliens--Wingnut and Screwloose--brainwashing the cadets to be their army and must call in the Turtles to defeat them.
Frip the Polarisoid arrives back on Earth with his family for a visit, and must ultimately ask the Turtles for help in reclaiming his camera while helping them stop Krang's latest plan to conquer the city