In the series, Leatherhead was a baby alligator that was owned by a kind boy until the boy's cruel parents found him and flushed him down their toilet into the sewer. He was discovered there by the Kraang, taken to their dimension, mutated, and experimented on. After suffering long and brutal torture, Leatherhead escaped back through the portal that connected Earth to Dimension X with a piece of the Kraang power cell. Returning to the sewers, he spent the next 6 months guarding the cell with a maze of booby-traps, swearing to keep it away from the Kraang to prevent their invasion from happening, even if it costs his own life.
He first appeared in "It Came From The Depths," where he attacked sewer workers near his lair, causing the Turtles to investigate and find him being attacked by the Kraang. The Turtles ended up springing into action and fended off the Kraang as Michelangelo suggested to take his unconscious body back to their lair. Once Leatherhead awoke, he started attacking the Turtles until he was tasered. Splinter learned about Leatherhead and his encounter with the Kraang as he told Michelangelo to befriend him and learn about what the Kraang are up to, having the other Turtles chain him up as a precaution. While the other Turtles went off to find the Kraang power cell, Michelangelo introduced himself, gave Leatherhead his name and befriended him as Splinter advised. When the other Turtles returned, they found that Leatherhead had been unchained and asked him about the Kraang. Leatherhead reacted savagely when they show him the power cell that he had hidden and went on a blind rampage until Splinter arrived and subdued him. Michealangelo began to feel sorry for Leatherhead and followed him to an abandoned subway car. After the other Turtles showed up and learned Leatherhead's history, a squad of Kraang arrived and attacked them all. Leatherhead volunteered to buy the Turtles some time so that Donatello could hook up the cell to the subway car. While the Turtles got away, Leatherhead defeated the Kraang.
In "TCRI," the Turtles lost the power cell to the Kraang. Leonardo suggested they should pay Leatherhead a visit, in order to solve where the Kraang could have taken the it. Leatherhead was awakened, and the Turtles tell him about the loss of the cell. Leatherhead tells them that all he remembers was a logo that the Kraang could operate under, and Donatello was able to track that logo to the TCRI work center in Brooklyn. Leatherhead helped them break into the building and kept the Kraang-droids busy while the Turtles went up to the top floor. By the time Leatherhead caught up with them, they were fighting Traag, who just came through the portal from Dimension X. All seemed lost until Leatherhead joined the fight. He grabbed Traag by the feet and threw him towards the portal. However, something else, possibly Granitor, began to come through the portal, and in spite of Michelangelo's protests, Leatherhead said farewell before pulling Traag into the portal with him and disappearing into Dimension X.
In "Mazes & Mutants," a mutant house sparrow named Sir Malachi tricked the Turtles into playing an illusionary world created by their board game, using Leatherhead's likeness as the dragon guarding "Princess April" from them. Acting as Sir Malachi's dragon, this illusion of Leatherhead could breathe fire and possesses none of his personality traits except for his ferocity. Later after the Turtles exposed Sir Malachi's illusions as being false, the illusion of Leatherhead (along with Dr. Tyler Rockwell as "Monkey Goblins") were seen following Sir Malachi's departure as they leave the sewer.
In "Into Dimension X," it was revealed that due to Dimension X's Time Differential, Leatherhead has aged up considerably, receiving more scars than before, his scales turning grey and dull, and carrying a crystal staff around with him like a cane. (It is possibly that it may be an even bigger source than the Kraang's power cell he once held onto.) After being hunted by the Kraang for what can only be described as many, many years in Dimension X, before being captured yet again, Leatherhead sent out a distress signal to the Turtles that the Kraang have perfected the instability of their mutagen and were preparing to invade Earth to terraform the planet into one resembling that of Dimension X. With Michelangelo's knowledge of Dimension X helping them (after Michelangelo spent a few weeks in Dimension X), the Turtles managed to rescue Leatherhead and together they managed to delay the Kraang's plans for the invasion, but only temporarily.
In "Invasion: Part 2," Leatherhead fought off several Kraangdroids in the sewer when they were about to kill Splinter. He teamed up with Splinter so that he could find his friends and stop the Shredder. As Splinter was being overpowered and brutally beaten by Shredder, Leatherhead took Shredder by surprise, biting him in the stomach and brutally thrashing and beating him. As he checked on Splinter, Shredder managed to power through Leatherhead's ambush, beating and injuring him in short-order. Leatherhead was last seen collapsing into a pit that was baited to trap Leonardo.
Leatherhead made his return in Season 3 as a member of the Mighty Mutanimals. While what happened between his appearances is unknown, it was learned that he is 2nd in command of the group and is shown to have a good relationship with Slash.