Hamato Yoshi / Splinter - Oroku and Hamato were raised in Japan as adoptive brothers and very good friends, and the two learned, exercised and became Masters in the art of Ninjitsu. However, their companionship suffered a great strain when they both fell in love with the very same woman, Tang Shen. They constantly competed for her attention, but she chose Hamato in the very end. Jealous, Oroku began harassing Hamato, insulting him and purposely trying to get him angry. This eventually culminated when Oroku learned of his true heritage and restored his birth clan as "the Shredder". Breaking into Hamato's own house and challenging him to a mortal duel, both men engaged in battle, and the house soon caught fire in the process (due to the fact that some burning candles were left laying around at the time), killing Tang Shen and horridly burning the Shredder's face. The latter found Miwa and secretly took her in, raising her as his own daughter and telling her many lies about what Hamato "did". Sixteen years later, the Shredder discovers that Splinter is hiding out in New York City, and he leaves Japan (along with his deployed Foot Ninja) to finish him off. The two finally meet again in "Booyaka-Showdown, Part 2" and duel with each other in The Foot Headquarters. The Shredder soon reveals to Splinter that his daughter is indeed alive, and he attempts to have her kill Splinter when she shows up. With this revelation, it is likely that Splinter despises The Shredder even more than he formerly did. In "The Manhattan Project", the two were excepted to a duel in Shredder's Hideout when Splinter was recaptured, only to be rescued by the Turtles. In Annihilation Earth, Shredder and Splinter form a temporary alliance to fight the Triceratons only for Shredder to betray him when Splinter tried to save the earth by shutting off the black hole generator. Shredder showed no shame as he doomed the planet stating his revenge was more important than the world. However, in Earth's Last Stand the turtles time travel and manage to warn Splinter about Shredder's betrayal and he is livid at Shredder's actions. After a fierce battle, Shredder is given a well deserved beating by Splinter resulting in him having to be taken away by Tiger Claw.
The Turtles - Since they are affiliated with Splinter (as his disciples), Shredder views the Turtles as enemies, and he orders his henchmen to find and kill them throughout the entire series. However, out of the four times that The Shredder has encountered them, he's let them live only for the purpose of interrogating them (which hasn't yet happened).
- Leonardo - Out of all of the turtles, Shredder has had the most interactions with Leo; each of them highly antagonistic and adversarial. In Wormquake!, Shredder taunts him to watch Splinter die when he had Tiger Claw capture and poison the ninjitsu master, also telling him that it will be the last fight he ever sees. In The Legend of the Kuro Kabuto, Leo made a deal with Shredder involving the exchanging of Karai (which turned out to be a bomb) for the Kuro Kabuto, but Shredder attacks him, refusing to let the young ninja leave without a fight. In The Invasion, when Shredder learns that Leo has been separated from his brothers, Shredder tracks him down and sends Foot-bots after him, sadistically wanting to "see him suffer" before killing him. During this time, he claims that Leo is foolish and overconfident due to his youth. When Leo defeats all of Shredder's lieutenants, Shredder himself knocks him unconscious and has him taken away. In Serpent Hunt, Leo briefly argues with Shredder about his "parentage" over Karai. Recently, in Casey Jones VS. The Underworld, as Leo engages Shredder in another ferocious battle at the Auman Chemicals factory, he claims that he is going to end Shredder once and for all. Because of this, Shredder may despise Leo more than any of the other turtles while Leo may show the greatest amount of disdain for Shredder compared to all of his other enemies.
- Donatello - Shredder and Donnie have more recently met. He, like his brothers, despises Shredder for the things he's done to their sensei and for trying to kill him and his brothers.
- Michelangelo - When Shredder and Mikey met, he, along with his brothers, is now at war with Shredder and his Foot Clan. Mikey hates Shredder for what he's done to his father, Splinter, trying to kill him and his brothers, and for all his misdeeds and raising their sister, Karai, against them.
- Raphael - When Shredder and Raph met as soon as they saw each other, they knew they were enemies. Raph hates Shredder (not only for trying to kill him - in Raph's mind that is probably not so bad), but for harming his brothers, and everything he's done to his father, Splinter. He was the first turtle to suggest that they take out Shredder at the pier in Enemy of My Enemy.
April O'Neil - Shredder learned from his Kraang hostage that April is not only a friend of the Turtles, but also the ingredient to the Kraang's invasion that the Turtles are guarding from the Kraang, so with the Kraang's help, he use her as bait to lure Splinter out of hiding. Due to this, it is quite probable that April dislikes him greatly.
Casey Jones - Shredder almost caught Casey spying on the meeting at Vizioso's restaurant but excepted the boy's lie that he was a bus-boy and kicked him out. Later, at the Auman chemicals factory, Casey stops Shredder in his vigilante gear and attempts to fight him, but Shredder is unstoppable for Casey and unmasks him as the same boy from the restaurant.
Hamato Miwa / Karai- She was once Splinter's daughter, Miwa, who Shredder kidnapped after the events of his and Splinter's final battle, named her Karai, and raised her as his own child. However, it is uncertain that Saki truly loves Karai like she does him. In Season 2, after she finds out that Saki is not her true father, she betrays him and he has her locked away. In "Vengeance is Mine," Shredder did not want Tiger Claw to kill Karai when she got out. When Shredder wanted Karai to understand what he had to do, Karai told Shredder that he is not her father. After the Turtles freed Karai, Shredder states to Tiger Claw that Karai will want to have her revenge on him. When Karai arrives to get her revenge on Shredder, she ends up overwhelmed by Shredder who manages to defeat her. Shredder then plans to use Karai as bait so that he can have the Turtles fall into the mutagen vat filled with snake DNA that Stockman had placed in there. During Shredder's fight with Splinter, Shredder tried to stop Leonardo from freeing Karai only for her to fall into the mutagen vat and emerge as a snake-like mutant much to the dismay of Shredder and Splinter. Shredder blamed Splinter for Karai's mutation as the resulting battle ends up destroying Stockman's lab. He escapes after vowing to avenge Karai. This event reveals that deespite Shredder's cold attitude and lack of empathy to Karai, he truly saw her as his daughter and loved her dearly.
The Mighty Mutanimals - Due to their connections with the Turtles, Shredder probably considers te Mutanimals as threats as well.
- Slash - Shredder and Slash don't interact much except when the dishonorable ninja used his Mind Control Worms on him to atack Splinter and abduct Raph, but Slash breaks free of from Shredder's control with the hel of the Turtles and the other Mutanimals, then drop a huge statue on the crimelord.
- Leatherhead - In The Invasion, As Shredder attempts to kill Splinter, Leatherhead interferes, bites Shredder's stomach and threw him into the building. As Leatherhead attempts to free Splinter, Shredder fought Leatherhead and kicks him down into the pit.
The Foot Clan- Oroku was born to the Foot's leader Oroku Kaji as his heir, until the entire clan was wiped out by the opposing Hamato Clan and Oroku adopted and raised by Hamato Yuuta as a brother to Hamato Yoshi. However, the clan was restored when Oroku discovered his true heritage and crowned himself the Foot's new leader with its signature artifact, the Kuro Kabuto.
- Chris Bradford / Dogpound / Rahzar- Shredder trained Bradford in his own image as the Foot's top lieutenant and second best fighter, maintaining his rank and respect to the entire clan.
- Xever Montes / Fishface- Shredder freed Montes from prison after the street thug was caught burglarizing his property by the police, mainly because he found his burglarizing skills very useful to his clan, as well as the fact that Montes likes having a job where he gets to crack skulls almost everyday.
- Baxter Stockman / Stockman-Fly- Shredder spared Stockman after the inventor's M.O.U.S.E.R.S's interfered with his feud against the Turtles, mainly because he found his talented inventing skills very useful to his clan, which led to several improvements, such as making Fishface a pair of robotic legs, thus making the latter a more powerful combatant. Shredder, however, for the most part, cares little for Stockman and he probably chose to dislike him even more after the scientist trapped Dogpound and Fishface in the "Maze of Doom". Stockman still buys back Shredder's favor by creating a formidable or even decent mutant army for him.
- Tiger Claw- Shredder found Tiger Claw in Japan and found the bounty hunter's skills very useful, thus he made the feline fatality his second-in-command. Though Tiger Claw is unimpressed with the Foot Clan, he accepts the job regardless. Even after Tiger Claw returned from the stomach of the Kraathatrogon, he was reinstated as the second-in-command, showing how much Shredder respects his ally's skills.
- Ivan Steranko / Rocksteady- Shredder and Steranko have been business partners in the mafia, but Shredder doesn't always trust the arms dealer that much. This distrust escalated after Shredder found out that he sent Zeck to steal the Kuro Kabuto and was hunting Karai, and had Steranko mutated and forced to work for him as payment for his treachery.
- Anton Zeck / Bebop- Shredder was almost robbed by Zeck of the Kuro Kabuto, which the Turtles return to him in exchange for Karai. Upon finding out that Zeck was employed by Steranko, Shredder proceeds to have the thief punished for stealing his helmet and hunting Karai without consent by mutating and employing him and Steranko into his service.
- Don Vizioso- Shredder and Vizioso have been business partners in the mafia like he was with Steranko, and during Shredder's meeting with the food critic at his restaurant, he announces that the Kraang have given him the opportunity to gain control over much of the crime groups in the city. Thus, he asks Vizioso to join in by sharing control of his mob to him, and after being proven a point, Visiozo complies.
The Purple Dragons- Shredder has allied the Foot with the Purple Dragons on many occasions in the past.
- Hun- Shredder is helped by Hun to retrieve the chemical from the Aumen Chemicals Factory for his mind control serum.
The Kraang- Shredder made an alliance with the Kraang only to get him closer to Splinter. But his true intentions were to use their technology and when the time is right he will betray them
Tang Shen - A woman that both Oroku Saki and Hamato Yoshi fell in love with. She chose Yoshi over Saki, however, and in a fit of jealousy and rage, he attacked Yoshi one night and apparently killed Tang Shen in the process.