She grew up with Catelyn at Riverrun, where she fell in love with Petyr Baelish. When the girls grew older, Lysa went to a drunk Petyr and had sex with him. He thought she was Catelyn. Baelish is thrown out when a pregnant Lysa went to her father and asked to marry him. Instead her father married her to Jon Arryn of the Eyrie, a man old enough to be her grandfather and the keeper of the Vale of Arryn. Lysa's father, Hoster Tully made marriage to a soiled Lysa as the price of the Riverrun alliance and troops for Robert's Rebellion. Lysa believed that marriage would give her child a name, but her father gave her a potion to cause a miscarriage. This maybe why she is so obsessive a mother, and she has never forgiven her father. Lysa had many miscarriages and only gave Jon Arryn one son, Robert Arryn, who is a sickly child. After Jon Arryn died in King's Landing, Lysa took Robert and fled to the Eyrie, where she has been cowering since.
Lysa sent a message secretly to Catelyn Stark (it was in a coded message hidden in the false bottom of a box left in the chamber of Maester Luwin of Winterfell). In the letter she accused the Lannisters of being responsible for her husband's death. This was a good part of the reason why Lord Eddard Stark accepted the position as Hand of the King, to investigate the plot. There was also the information from Petyr Baelish that the knife used in the assassination attempt on Bran, was owned by Tyrion Lannister. These facts culminated in Catelyn Stark taking Tyrion Lannister prisoner and putting him on trial, which began the first fighting in the War of the Five Kings. She has refused to send the Eyrie's troops to help anyone in this war, though she did nearly execute Tyrion Lannister when Catelyn brought him to her as a captive.
As a wealthy, still fertile widow, with only a sickly child, Lysa is seen as a very eligible match by all her bannermen. Since the death of her husband she has been continually surrounded by suitors, try to court her favor. She enjoys the flattery, but her heart belongs to another.
In A Storm of Swords, Petyr Baelish takes Sansa to the Eyrie. Lysa meets him on the way, at the Fingers and it is revealed that they have long planned to be married. They do immediately. At the Eyrie, Sansa learns that Petyr convinced Lysa that he was in love with her, so she murdered Jon Arryn herself. Jon had been planning to separate her from Robert, sending him to foster with Stannis Baratheon at Dragonstone.
When Lysa sees Petyr Baelish impulsively kiss Sansa Stark, she attempts to kill her niece. She takes Sansa to the Moon Door and tries to throw her out while her minstrel sings loudly to drown out Sansa's calls for help. Petyr comes and talks her into freeing Sansa, but when Lysa starts confessing to how they murdered her husband, he realizes that she is now a liability and pushes her out of the tower, killing her. He then blames the singer Marillion.