As a child, Uryū mostly interacted and trained with his grandfather, Soken Ishida who taught him everything he knows and took Uryū in a trip to Amegakure to visit some of his friends who Soken asked them to train Uryū everything they know about the rain release, after 2 years of practicing he learned all there's to know about the rain arts. His father, Ryuken Ishida, was less than enthusiastic about being a Hyūga, claiming that it was not a profitable occupation. They do not appear to be on very good terms as a result, given Uryū's casual use of his father's given name. Soken understands Ryuken's reasoning, since being a Hyūga is more about justice than material rewards and Ryuken has a family to support. Soken told Uryū that he would someday understand his father's motives, but thus far this is not the case.
At a fairly young age, Uryū's grandfather was killed by Uchiha clan members right in front of him while he was not able to do a thing to protect him. This is one of the reasons why he hates the Uchiha, who did not come to rescue Soken in time.
Uryū is later seen walking down a street and staring at Ichigo Kurosaki. He saves a Plus from a Ninja and goes to a location where he can see the Plus. He then spots Ichigo again as Ichigo performs a Sharingan eye technique on the Plus. Later in the Ninja academy, he is again seen near Ichigo, who is dragged off by Rukia Kuchiki to defeat a ninja. However, Uryū defeats this ninja before them, and when Rukia and Ichigo get there they begin arguing with each other. Uryū approaches them and states that a ninja is here - just before Rukia senses the presence of the ninja upon his arrival. After Ichigo asks Rukia which way the ninja is, Uryū mocks him for not being able to locate something as simple as that and tells him he should not even call himself a Uchiha. Uryū then uses his Byakugan, tracking the ninja and using his normal bow "Kujaku" to shoot an arrow killing the ninja. Ichigo asks him what he is and Uryū introduces himself, stating that he is a Hyūga and that he hates the Uchiha. Ichigo is confused by this statement and Uryū tells him that he hates him for being a Uchiha.
Uryū is later seen in his classroom in the academy, and as he tries to leave, a girl named Michiru Ogawa hands him a ripped doll to fix. He then takes a sewing set out and easily (but with great drama) repairs the broken doll. As he heads home, he spots Ichigo following him. He mocks Ichigo for not being able to hide his chakra and for his inability to locate others with high chakra reserves. He then tells Ichigo that since the day he entered school, he knew of his high chakra level, that he knew when he became a powerful Uchiha and even knows Rukia's true identity. Uryū then draws out something called Reiraku and states that it is something that compresses and visualizes the chakra aura in the atmosphere. He again mocks Ichigo's ignorance, and, grabbing hold of Ichigo's Reiraku, points out that those of Uchiha are colored red. He then tells him that he is a Hyuga and that he holds the power to kill Powerful ninjas as well as Ichigo, and asks Ichigo to fight him to show the difference in their strength. Ichigo tells him the idea of competing against him is stupid, as he has nothing to do with his grudge against the Uchiha. However, Uryū is able to provoke him by stating that he is only a temporary asset to the Uchiha who cannot even do anything without Rukia around. Ichigo tells him that he will give this competition a shot and activates his Sharingan. He then asks Uryū for the rules of this fight. Uryu takes some Ninja robber's bait out and states that he is going to bring powerful ninjas into the town, and that whoever kills the most ninjas within twenty-four hours is the winner. However, Ichigo protests against this idea as the people in Konoha will be put in danger, but Uryū tells him that caring for others is unnecessary and that either way he should be confident enough to save them all.
Ninjas begin breaking into Konoha Town and Uryū shoots the first one down. As he is doing this though Ichigo grabs him and tells him to bring the village back to normal. However, Uryū states that it is too late and that instead of focusing on him he should be focusing on the ninjas so he can save as many people as possible. He then tells him that foreign ninjas have a tendency to go after people with high chakra reserves and Ichigo realizes his family is in danger. He immediately runs off to save his family, missing what Uryū tries to tell him as he leaves. Uryū begins shooting ninjas from the high vantage point of a bridge, reaching up to eleven kills. After killing more and more ninjas, Uryū's shots begin to get weaker and he realizes that the numbers should not be this high. He decides not to complain though and remembers his mentor, telling him he has not made any mistakes and that he will avenge him.
Uryū then encounters Rukia. Uryū comments on the ninjas' current location being safe which prompts Rukia to question him, saying that it is because of Uryu starting the fight that the village is danger. He addresses Rukia, admitting that while he did start the fight, he will not allow anyone in the village to die even if Ichigo dies. Suddenly a weak ninja returns to attack. As Uryū is about to shoot the ninja, only for it to be swiftly killed by Ichigo as he arrives at the scene.
Ichigo starts arguing with Rukia while Uryū looks on. Irritated that they will not stop arguing, Uryū fires an arrow at Ichigo, who blocks it. Ichigo then insists that it is a battle between him and Uryū, and that the amount of ninja's they beat is irrelevant. Before Uryū can respond, Rukia points out that there is a large crack forming in the sky, and Uryū notes that the ninjas are converging upon it. Uryū begins to fire arrows into the group of ninjas and charges towards the ninjas, shouting that the Hyūga will be their opponent.
Ichigo learns about the fall of most of the Hyūga's at the hands of the Uchiha, he runs after Uryū and attacks several ninjas around him. Ichigo tells him that he does not know or care about whether the Uchiha or Hyuga were right and expresses his frustration at Uryū's methods, but is interrupted by him. Uryū tells him that he thought the Uchiha were correct, until his sensei was killed in front of him. Uryū tells Ichigo of his sensei's attempts to convince the Uchiha to work together with the remaining Hyuga, but he died fighting a group of Huge ninjas without achieving that goal. Uryu says that he must prove the strength of the Quincy to the Uchiha. Ichigo points out that his sensei's wish was to work together, not to prove the Hyūga's strength and asks if he will do that now, saying that fighting back to back is the best way to deal with the situation.
As Uryū dismisses the idea as nonsense, Ichigo attacks a ninja that had come up behind Uryū, who kills another ninja. Uryū insists that he is not cooperating, but that he simply had to kill it or else he would have been killed. Ichigo tells him that that is good enough. Ichigo states his own reluctance to work with Uryū, and asks him if he will cooperate. Uryū kills another ninja in reply. The pair agree to beat each other up after the ninja's have been dealt with, but as they are about to attack the horde of ninjas,a huge ninja rips apart the sky appearing out of nowhere. After they argue about how to deal with the remaining ninjas and that huge ninja, Uryū Tsumugiya, Tessai Tsukabishi, Jinta Hanakari, and Urahara arrive to fight the ninjas. Uryū's attention is then turned to the emerging huge ninja. Ichigo tells Uryū that there is no way they can figure out how to fight such a monster and that they will have to simply cut it repeatedly until it succumbs to its injuries. He charges towards the huge ninja, calling for Uryū to accompany him despite Uryū request for him to wait. Uryū fires an arrow at the ninja's neck but does little damage, confirming his self thoughts on how he will not be able to do much damage. He then checks on Ichigo's status and asks what was he thinking.In response to Uryū's questions, Ichigo tells him that he is alright and that he thought he could cut its feet off and work his way up to the head and kill it that way. Uryū complains about his way of thinking and places his hand on Ichigo's Katana. Uryū notices that Ichigo's power is flowing into his bow. Thinking about the differences between the fighting styles of the Hyuga and Uchiha, Uryū comes up with an idea to make use of Ichigo's large amount of power. As Ichigo is shocked to see the increased size of Uryū's bow and asks what happened to it, Uryū tells him his idea.
With Ichigo's Katana tied to his head, Uryū instructs a dubious Ichigo to increase his power to its maximum so that he can shoot an extremely large arrow at the huge ninja. Ichigo points out that he never controls his energy output and that if people say that his power is great then it must be at maximum all the time. When the ninja starts to charge a huge red chakra sphere, Uryū calls for Ichigo to connect his Katana to his body again but is surprised to find Ichigo rushing towards the ninja. Ichigo blocks the chakra sphere with his katana and Uryū notes that Ichigo's power increases as he resists the red chakra sphere. Ichigo repels the attack, injuring the ninja in the process. As the ninja retreats from the Konoha, Ichigo yells "Victory" and asks Uryū whether he is going to thank him for his help before collapsing. Uryū notices how Ichigo's Katana begins to lose its form. The energy released from Ichigo and his Katana causes Uryū's bow to grow again. Noting that it will explode, Uryū begins to fire arrows into the sky to release the excess power and to stabilize Ichigo, injuring himself. Ichigo tells him not to over do it, as he will lose his arm. Uryū tells him to make sure that he lives so that they he can beat him later. Uryū realizes his mistake for misunderstanding his sensei and for being so useless, asking to be forgiven for his mistake.