The Turtles: Leatherhead was rescued by the Turtles (mainly Mikey) when he was being chased by the Kraang. At first, excluding Mikey, they were wary about him because of his temper and size, but none the less, they see him as a valuable ally. Leatherhead sees them all as his only true friends that he can trust, and slowly starts opening up to them.
- Michelangelo: Out of all the Turtles, Leatherhead and Mikey have the closest friendship. Mikey was the first out of all his brothers to be willing to rescue Leatherhead from the Kraang. Despite his brothers' fears and warning that it wouldn't be a good idea, considering the mutant gator had a temper, Mikey managed to convince them to bring him back to the lair. While the other turtles went to look for the powercell, Mikey took the time to befriend Leatherhead. Leatherhead really opened up to Michelangelo and really liked how he gave him his name and his pizza noddle soup. Mikey went after Leatherhead when he went on a rampage and attacked his family, when Donnie showed the powercell to Leatherhead. When the Kraang attacked, Leatherhead handed the powercell to Mikey and his brothers and fought the Kraang so they could escape, because since the youngest turtle trusted him, he decided to trust him. Mikey is the only one of the Turtles who can calm down Leatherhead when he goes berserk. Leatherhead participated in helping the Turtles in TCRI, where he sacrificed himself so the turtles could escape. Mikey was the saddest of them all to see his friend go. The bond that the two formed helped Leatherhead learn to trust people, and made him want to defeat the Kraang even more. After Mikey finds out that Leatherhead is still alive in Dimension X, being held captive by the Kraang, he went to any lengths to free his friend. When the Turtles are rescued by the Mighty Mutanimals, Leatherhead and Mikey share a heartfelt moment, with Mikey about to cry to see his friend again. Through out the entire episode Leatherhead and Mikey hug every time they see each other.
- Donatello: Donnie has neutral feelings about Leatherhead. While he sees him as a valuable ally, Donnie's very terrified of Leatherhead; mostly because there's a running gag where whenever Leatherhead loses control, he grabs Donnie by the face and shakes him like a rag doll. Leatherhead has regretted this action though and he sees Donnie as a good friend, like he does all the Turtles.
Master Splinter: At first sight, Splinter fought Leatherhead and easily defeated him for almost killing his sons. In The Invasion, Leatherhead rescues Splinter from almost being captured by the Kraang. Later, Leatherhead fought on Splinter's side against the Shredder and knocked him with powerful bites down and threw him against a wall. Shredder, who seemed to be deafeated, attacked Leatherhead from behind and was able to throw the surprised Leatherhead off the building and into the river to his supposed death. This caused Splinter to attack the Shredder with great anger. This shows that Splinter has come to respect Leatherhead as a good friend.
- Slash: Leatherhead teams up with Slash as the second-in-command of The Mighty Mutanimals. In Clash of the Mutanimals, Leatherhead fought a mind-controlled Slash but was freed by Dr. Rockwell.
The Kraang: Leatherhead has an endless amount of hatred for the Kraang, much like Newtralizer for all the things they done to him. While they did take him in when he was a baby, they subjected him to several experiments which continuously haunt and torture Leatherhead to this day. Even hearing the word "Kraang" makes him go insane. The abuse he suffered from them caused him to go into uncontrollable rages especially when he has nightmares. He's determined to destroy them once and for all.
- Shredder: Leatherhead fought against Shredder and was even able to brutally crush him, until Shredder attacked him from behind and injured him with bis blades. Leatherhead was more then a match for Shredder but was at the end barely deafeated.
- Tiger Claw: Leatherhead and Tiger Claw never interact much. After fighting Slash, Tiger Claw threatens to kill Rockwell if Leatherhead makes his move.