After saving his partner Dosu from Rock Lee's lotus attack, he brutally fought off Sakura who attempted to prevent him from killing Sasuke. After the helpless Sakura lay beaten on the ground, he and his team had to fight Team Asuma. During the fight, Sasuke finally regained consciousness, and asked Sakura who had injured her. Zaku took the credit, and Sasuke proceeded to dislocate and greatly injure Zaku's shoulders. He was the only Sound ninja to fight Sasuke, as the others retreated. During his fight with Shino Aburame in the preliminary exams, he overcame the injuries to his shoulders and was able to use his arms to defend himself against Shino. Due to his cockiness, he attempted to attack both Shino and his approaching army of Kekai insects, not noticing that the chakra-eating bugs had already filled the tubes in his arms, preventing him from attacking and even more brutally crippling and preventing him from doing any damage in the future (In the manga, his right arm was blown off due to the kikai bugs Shino used to fill up Zaku's air tubes, and the left was kept intact but halfway sliced. In the anime both of his arms are left intact, but have numerous holes in them, achieving the same, albeit less gruesome, result). Dosu says he would avenge him (or rather, his severed arms), but failed to do so.
Zaku, along with Kin Tsuchi, is later murdered as a sacrifice for Orochimaru's Impure World Resurrection for the First and Second Hokages against the Third Hokage.