Ishizu first appears in episode 24. She claims her Millennium Necklace gives her the power to predict the future and to break the fourth wall, despite the fact it is blatantly obvious every character has this power. She rather carelessly gets the Egyptian God Cards stolen from her. She also lends Obelisk the Tormentor to Kaiba without considering that he would just keep the card rather than giving it back. Kaiba finally decides that she's not good at predicting the future when she predicts that in ten years Kaiba will open a dueling school and look exactly the same as he does now. In episode 26, she explains to Yami about his destiny, apparently "spoiling all of season 2" in the process, but it's not enough to please Yami, who wanted a flashback. However, the flashbacks she shows him turn out to be nothing more than two moments in his life where Yami was crying for a nipple: as a baby, and as the pharaoh during the Thief King's raid, although Ishizu admitted the latter was just her "screwing with him".
She also appears in Episode 32, claiming the giant rock is the only one that understands her and goes off and hides (senses) when she hears Bakura coming, not wanting to get involved in the actual plot. There might a be a possibility that she's a lesbian, according to Bakura's gaydar until its batteries ran out. However, the gaydar could have been pointing to the rock, implying that the Eygptian civilization was gay.
In the Yu-Gi-Oh! Abridged Third Anniversary Video, she and Espa Roba have a prediction war over whether or not Yu-Gi-Oh Abridged would be canceled after LittleKuriboh finished Season 2, but she dismisses his prediction as a fruitless attempt at creating hype. One of the Roba brothers offers to sell Ishizu the baby.
In episode 44, when Kaiba asks her why she doesn't have a catchphrase, she responds with "Because shut up." However, this is very confusing as the intent could have been either to show that she had a catchphrase or that she simply couldn't think of a good answer.