Immediately after the player claims the reward for Ishizu Ishtar's appropriate Character Unlock Mission, they will encounter Ishizu for the first time. She remains silent for a moment, before stating she didn't expect to ever stand on the "battlefield" again - something she did not expect from Kaiba. She then questions how she has her Millennium Necklace, having already given it to Yugi during Battle City, before she begins to wonder if this world has recreated the abilities she had during Battle City. Ishizu then wonders if this means Marik is in Duel World as well. She grows saddened, as she wonders if Kaiba has basically forced her to relive the horrors she faced back then.
Until the player manages to defeat Ishizu at least once, whenever they challenge Ishizu to a Duel, she says that she now understands that the player must defeat her if they are to proceed. She recognizes that this is her role in this world and prompts the player to defeat her in order to take control of their own destiny. However, she also warns the player that she will not make their Duel an easy one, claiming that the player will see that her strategies have no equal.
Until the player manages to defeat Ishizu at least once, whenever they lose to her, she announces that she won because her victory was never in doubt. She then offers the player a piece of advice: Although she has the power to see the future, that does not necessarily mean that there is only one, as the future can be changed. She reminds the player that they always have the power to change the future, and urges them to believe in their cards.
Upon Ishizu's first defeat, she will say, "Nicely done." She then tells the player that the path to the future is for them to choose, so they should choose wisely. However, she also tells them to not forget that she is forever a Duelist, as this means she may stand in their way again in the future. When that time comes, she says, the both of them should have an honorable Duel.
After the player redeems their final unclaimed reward for Ishizu Ishtar's Character Unlock Missions, they will encounter Ishizu again, who tells the player that she attained something in her previous Duel: the light of hope. She continues by saying that even if the future is overshadowed by despair, people have the ability to change the future. She admits she cannot foresee what awaits people in Duel World, but she will keep fighting for a brighter tomorrow, and that she'll battle using her cards (which includes the "Blast Held by a Tribute" card).
Most of the time when Ishizu declares an attack with that monster, she announces "Gravekeeper's Spear Soldier, attack!" followed by "Lunging Spear Assault!"
When Ishizu Summons "Keldo", she announces "Come to me Keldo!"
When Ishizu Summons "Zolga", she announces "Come, Zolga!"
When Ishizu activates "Blast Held by a Tribute", she says "I caught you!" then she announces "I activate my Trap Card! Blast Held by a Tribute!" followed by "The Tribute Summoned monster is destroyed the instant it attacks!"
When Ishizu activates "Cestus of Dagla", she announces "The Equip Spell, Cestus of Dagla!" and when she attacks she announces " "I activate the Equip Spell, Cestus of Dagla."
When Ishizu activates "Gravekeeper's Stele", she announces "I activate the Spell Card, Gravekeeper's Stele." followed by "I add "Gravekeeper" monsters in my Graveyard to my hand."