Boss levels in Mega Man X6 are tied to the number of Nightmare Souls the player has obtained, up to a max of Level 4 at 5,000 Nightmare Souls. If Nightmare Zero is beaten at Level 4, Zero's black armor from previous games is unlocked. This armor is only normally unlockable with a cheat code entered at the title screen (L/L/L/ZR). Due to an oversight, the final stage unlocks automatically when the player obtains only 3,000 Nightmare Souls, meaning that Nightmare Zero is impossible to fight at Level 4 without a GameShark code (300CCF5F 0003 for the US version of the game) since he becomes unavailable when the final stage is unlocked.

An electric guitar was added to the intro stage theme in the US and EU releases.

Like Serges in Mega Man X2, there is a theory that Isoc is Dr. Wily. A quote from Haruki Suetsugu in the Mega Man X complete works suggests their similarities go deeper, stating, "I was thinking about a certain scientist while designing this character..."

Metal Shark Player's Japanese name is actually Metal Shark Prayer. His English name is the result of a mistranslation of R and L being identical in Japanese. The reason he is called Prayer is because he resurrects other Mavericks (these being Sting Chameleon, Magna Centipede, and Blast Hornet), thus he "prays". It is also worth mentioning that when he resurrects the Mavericks, he shouts their Japanese names.

The Wolfoid Reploids that can be saved are all named after characters from other Capcom franchises.
• Maringa - Morrigan, Darkstalkers
• Ryu - Street Fighter
• Ken - Street Fighter
• Chun - Chun-Li, Street Fighter
• Guy - Final Fight
• Nina - Breath of Fire
• Batsu - Rival Schools
• Data - Mega Man Legends
• Regina - Dino Crisis
• Leon - Resident Evil
• Sam - Samanosuke, Onimusha
• Naruho - Naruhodou (Known as Phoenix Wright in English), Ace Attorney
• Dante - Devil May Cry
• Gomez - El Dorado Gate
• Arthur - Ghosts 'n Goblins