After killing a certain amount of enemies the arm lights up red and he can perform Grip of the Murder to perform a devastating attack. The effect of the curse makes him more powerful or weaker at certain moments in the game. This makes Ryu feel the pain of each victim as he kills someone. Early in the game he receives an evil curse that fuses his dragon sword into his arm, causing it to pulsate with veins. Many of the opponents are mechanical and equipped with guns. The ninja can fly down and attack from the air, use a new technique to climb walls using his kunai with a quick succession of buttons, or sneak up from behind and perform a stealth kill. Enemies in the air can be attacked using an auto-targeting bow with unlimited ammo and there are also shurikens. Incoming attacks can be blocked and there is a new slide manoeuvre and a visual camera trick in slow motion when he performs a body-piercing move, along with finishers. Moves are performed with a combination of weak and strong attacks.

Just like the other titles in the series gameplay is centered around fast-paced combat with a quick succession of moves to build up combos and fight off multiple enemies at the same time. The story no longer involves the struggle with Fiends and Archfiends from the previous games. From London the journey eventually takes him to a city in the Rub' al Khali desert, Abysmo Island in the Indian Ocean, Hayabusa Village in Japan, the Howard Phillips Plains in Antarctica, the Pacific Ocean, and finally back in Tokyo, Japan. Later on in the game it is revealed the group behind the attack is a cult of alchemists who want to establish a new world order with Ryu as the catalyst. He travels to London from Japan but has no intention of just surrendering. In a video they declare they want Hayabusa handed to them.

Soon after it is revealed through a flashback that he was contacted by the government because an unknown group launched a terrorist attack in London and took control of the area surrounding the prime minister's residence, taking him hostage. The game starts in medias res with Ryu attacking a giant creature through a quick time event. Ninja Gaiden 3 is the third main game in the series since the reboot in 2004 and once again stars ninja Ryu Hayabusa as the protagonist.

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