Every season has a main antagonist. Garmadon, the Overlord, and Pythor are the most recurring.
- Pilot: Lord Garmadon commands Samukai and the Skulkin to steal the Golden Weapons of Spinjitzu, so he may create a portal to escape the Underworld.
- Season 1 (Rise of the Snakes): Pythor, the last of the Anacondrai who unites four other Serpentine tribes to free their progenitor, the Great Devourer, and wage war on humanity.
- Season 2 (Legacy of the Golden Ninja): Garmadon merges the Golden Weapons and takes over the Serpentine, intending to stop his prophesied defeat at the hands of Lloyd. After losing control of the Serpentine to Skales and finding the Dark Island, Garmadon is demoted to The Heavy for the Overlord, who resurrects the Stone Army to serve him before possessing Garmadon himself by the finale.
- Season 3 (Rebooted): The Overlord is brought back in digital form by Pythor, creating the Nindroids and stealing Lloyd's Golden Power to become the Golden Master.
- Season 4 (Tournament of Elements): Master Chen, who organizes the titular tournament to steal the contestants' elemental powers and turn his followers into Anacondrai warriors.
- Season 5 (Possession): Morro, a former student of Wu who was denied the mantle of Green Ninja and returns as a ghost, possessing Lloyd after escaping from the Cursed Realm. He seeks to free his mistress, the Preeminent (the Cursed Realm itself), so they may curse the other Sixteen Realms.
- Season 6 (Skybound): Nadakhan, the djinn captain of the Sky Pirates. He seeks to marry Nya so he may gain infinite wishes, stealing the ninjas' souls to do so, with the goal of recreating his realm that was destroyed by the Preeminent's death.
- Day of the Departed special: Master Yang, who brings back the ghosts of past villains (Samukai, General Kozu, General Cryptor, Master Chen, a reformed Morro, and a still-living Pythor) to distract the ninja while he attempts to resurrect himself.
- Season 7 (The Hands Of Time): The Time Twins, Krux and Acronix, the Elemental Masters of Time. The two reunite in the present, using their Vermillion Serpentine to recover their powers and travel back to the time of their defeat.
- Season 8 (Sons of Garmadon): The Quiet One/Harumi, the leader of the titular cult who seeks to resurrect Garmadon's evil side using the Oni Masks.
- Season 9 (Hunted): Lord Garmadon and the Sons of Garmadon rule the now-dystopian Ninjago. Meanwhile, Wu and most of the ninja are being hunted in the First Realm by the Iron Baron and the Dragon Hunters and must overthrow his rule before returning to confront Garmadon.
- Season 10 (March of the Oni): The Omega, the leader of the Oni that the Iron Baron claimed to have defeated, who attempt to conquer the Sixteen Realms.
- Season 11 (Secrets of Forbidden Spinjitzu):
- Fire Chapter: Aspheera, the Serpentine witch-empress of the Pyro Vipers who wants revenge on Wu for locking her away.
- Ice Chapter: General Vex, who manipulates the amnesiac Zane into becoming the Ice Emperor and conquering the Never Realm.
- Season 12 (Prime Empire): Unagami, the A.I. emperor of the titular video game who wants revenge on his creator for abandoning him, turning players into energy to power his portal to the real world.
- Season 13 (Master of the Mountain): The Skull Sorcerer/King Vangeles, who uses the Skull of Hazza D'ur to enslave the Geckles and Munce.
- The Island: Chief Mammatus is the leader of the Keepers, who capture the ninja after assuming they intend to steal the amulet they protect. The Keepers eventually attempt to sacrifice them in order to appease the evil storm spirit Wojira (actually a fake created by Ronin to scam the Keepers out of their treasures).
- Season 14 (Seabound): Prince Kalmaar of the Merlopians, who overthrows his father and seeks to awaken Wojira so he may exterminate the surface-dwellers.
- Season 15 (Crystalized): The Crystal King, who is in reality yet another identity of the Overlord.
