Before the zombie apocalypse, Andrea was a civil rights attorney and was struggling to build a proper relationship with her younger sister Amy. The outbreak began as Andrea was on her way to Amy's college and the sisters found themselves stranded in Atlanta. They would be rescued by Dale Horvath and formed a close bond with him over the coming months as they joined with a group of survivors fleeing the city.
Andrea would meet Rick Grimes after he rode into Atlanta on horseback and had to be rescued from a massive swarm of zombies. She and the other members of her scavenging party quickly found themselves following Rick's lead after he handcuffed an out-of-control Merle Dixon to a pipe on the roof of a department store. Thanks to Rick's quick thinking and natural leadership, Andrea and the others (minus Merle) escaped the city and returned to the camp. A couple of days later, however, tragedy would strike as a horde of walkers attacked the camp and killed several people, including Andrea's sister Amy. Andrea was consumed with rage and grief, refusing to let anyone touch Amy's body as she held it in her arms. As Amy reanimated as a walker, Andrea said her final tearful farewell before shooting her sister through the head.
After the Atlanta camp divided, Andrea stayed with Rick's group as they headed for the Centre of Disease Control. Dr. Edwin Jenner, the only CDC staff member left in the facility, hesitantly allowed the survivors inside and offered them food and shelter. He later explained what little he knew about the zombie plague and how far it had spread, causing Andrea to fall further into despair at the realisation that the human race was doomed. When Jenner revealed that the CDC building was going to self-destruct, Andrea decided that there was nothing left worth living for and opted to remain inside when the facility exploded. However, her decision left Dale bitter and angry at Andrea for coming into his life and making him care about her, and so he decided he would stay and die with her. This caused Andrea to reconsider as she didn't want to be responsible for Dale's death, and so the pair fled the CDC just before the self-destruct.
Feelings between Andrea and Dale became tense for some time following the CDC as Andrea felt betrayed by Dale for taking away her choice to die a quick death, but the two would reconcile after the survivors made camp at the Greene family farm. While staying at the farm, Andrea spent much of her time practising how to shoot properly and keeping watch atop Dale's RV. After Beth Greene fell into depression following the loss of her mother, Andrea, who was all too familiar with the despair that the zombie-dominated world wrought, believes that the best way for Beth to deal with the situation is to make her own choice about whether or not to commit suicide, undermining Lori and Maggie's attempts to protect Beth so that she can decide for herself. Indeed, Beth does attempt to kill herself by cutting her wrist with a shard of glass, but the cut isn't deep and she sobbingly apologises soon after, indicating that she wants to continue living.
One night, a massive herd of walkers descends upon the Greene farm, forcing the survivors to flee. During the battle against the swarming undead, Andrea becomes separated from the rest of the group and flees into the forest alone. After many hours of running for her life and exhausting her body and ammunition, Andrea almost falls prey to a walker when she is suddenly rescued by a mysterious hooded figure carrying a katana sword. This figure, Michonne, remains with Andrea and the pair struggle to survive on their own for the next ten months. One day, they discover a crashed helicopter in the forest and another group of survivors investigating the wreckage. The pair are discovered by the group who, to Andrea's surprise, are being led by Merle Dixon.
Andrea and Michonne are taken to the town of Woodbury by Merle and after receiving much-needed rest and medical treatment she is introduced to The Governor, leader of the township. The Governor invites the pair to stay and Andrea is tempted by the offer, but Michonne does not trust the Governor and is eager to leave. Things become tense between them as Andrea continues to get comfortable with the Governor, even after seeing that he has set up a stadium for people to fight against walkers.
Andrea starts to question her decision to stay in Woodbury after the town is invaded by her former friends from the Atlanta group, who have come in search of Glenn and Maggie who were abducted by Merle. After a series of struggles between Rick's group and the Governor's men, Andrea is torn between her desire to settle into the sanctity of Woodbury and her loyalty to her friends. It later becomes apparent that the Governor is on the warpath and will stop at nothing to slaughter Rick's group and take their prison sanctuary. When Andrea tries to rejoin her friends at the prison, the Governor goes after her personally, hunting her down and dragging her back to Woodbury.
In the last episode of Season 3, "Welcome To The Tombs", Andrea is tied up inside the Governor's secret torture chamber. The Governor decides to punish Andrea and his aide Milton Mamet by stabbing Milton and leaving him to reanimate then devour Andrea. Before dying of blood loss, Milton informs Andrea that there is a pair of pliers under her chair that he had dropped earlier and that she should use them to free herself before he turns. Andrea struggles to pick up the pliers with her boots and manages to get them off to help her grasp the tool. Unfortunately, by the time she gets a hold of the pliers and frees herself, Milton has turned into a zombie and attacks her. Andrea puts down the undead Milton, but not before she is bitten on the shoulder.
Later, Rick, Daryl and Michonne arrive in Woodbury and find the torture chamber where Andrea is slumped against the wall. They see that she is alive but has been bitten and thus doomed to reanimate. Andrea requests to end her life before she turns and Rick grants her wish by handing her his revolver. Michonne stays with Andrea as she commits suicide and later Rick takes Andrea's body back to the prison for a proper burial.