Lori is a strong, generous, independent, and emotional woman, but is also shown to be difficult and demanding at times. Having believed her husband to be dead and that the world was coming to an end, and trying her best to keep herself and Carl safe, Lori became extremely vulnerable and lonely. During this time she began a relationship with Shane, something that would cause her difficulty throughout the remainder of her life. With Rick's eventual return, she found herself with both extreme happiness and extreme guilt. She becomes torn between her husband and Shane; realizing they were both essential to her survival. However, her actions put Rick and Shane at odds, significantly more so with the revealing of her pregnancy.
Before the undead apocalypse, the Grimes were just another normal suburban family. However, shortly before Rick was injured in the line of duty and left in a coma, he and Lori were having marital difficulties; Lori would often confront Rick about why he chose not to discuss his feelings with her and a rift was starting to form between them. Not long after Rick was hospitalized, the zombie outbreak took place and chaos ensued as law enforcement and the military fell to the undead. Lori and Carl were taken out of King County by Rick's friend and partner Shane and they attempted to reach Atlanta, soon encountering other survivors who were also heading there as well as those fleeing from the city. During this time, Lori believed Rick to be dead after Shane had told her that the hospital he was in had been overrun. As she struggled to cope with the ever-worsening situation she was in, she found comfort in knowing that Shane was there to protect her and Carl and so she and Shane started becoming intimate with one another.
Months later, Lori and Carl are stunned to find Rick walking into their camp alive and well. Rick and Lori soon re-establish their relationship and Lori tells Shane privately that their affair is over, expressing her anger over Shane telling her that Rick was dead. This creates tension between the two and causes Shane to become increasingly jealous of Rick, even to the point where he contemplates murdering his old friend.
When the group of survivors become divided following a zombie attack on the camp, Lori joins Rick's group heading for the Center for Disease Control, a lead which turns out to be a dead end. While the group enjoy brief shelter with the CDC's lone occupant Dr. Edwin Jenner, they flee when they discover that the facility is set to self-destruct. Most of the group escape and hit the road once more, eventually finding their way to the Greene family farm after Carl is accidentally shot in the woods. Hershel Greene, a former veterinarian, is able to save Carl after Shane recovers medical supplies from an abandoned high school, and though he is hesitant to offer shelter to the group, he and Rick are able to make an arrangement and the group make camp adjacent to the Greene house.
During the group's time on the farm, Lori discovers that she is pregnant. She tries to hide her condition from Rick and Shane for a time but is forced to come clean by Glenn (who she confided in and asked to pick up pregnancy testers and sanitary towels from a pharmacy). The rift between Rick and Shane reaches the point of no return after this revelation as there is every possibility that the baby was conceived between Lori and Shane but no way to be certain. As far as Rick is concerned, the child is his regardless of who the biological father truly is, but Shane becomes more and more determined to take Lori back and get rid of Rick.
The tension between Rick and Shane eventually reaches breaking point and one night Shane lures Rick out into the woods in order to kill him. Rick is ready for Shane and kills him, but a short while after their showdown the farm is attacked by a massive herd of zombies. Most of the group escape, but they find themselves lost on the road in increasingly hostile territory and winter fast approaching. Rick reveals to Lori that he killed Shane and also reveals to her and the rest of the group what Dr. Jenner told him at the CDC, that everyone is infected with the zombie condition and that they will all turn no matter how they die.
Over the winter, Lori and Rick become increasingly distant as Rick struggles to try and keep the group alive and together. The group eventually find the prison where they decide to take up residence, but there is still a large zombie presence in the facility and Lori is unable to help as she is in the last days of her pregnancy. She fears how long her child will last in this undead world and also fears that the baby could be stillborn, wondering if it would turn into a zombie inside her and tear its way out of her.
In the third season episode "Killer Within", Lori, Carl and Maggie are cut off from the others inside the walker-infested crypts when Lori suddenly goes into labour. Carl finds them a safe place inside the boiler room. Lori starts losing too much blood and Maggie tells her that she needs to have a C-section or else the baby will die. Lori makes the decision to have her abdomen cut open so the baby can be removed. She says her final goodbyes and hugs Carl, telling him to not change what he is: a good boy. "You're the best thing I've ever done", Lori tells her son. Then, Maggie reluctantly cuts her open, causing Lori to die from blood loss as Maggie delivers the baby. Maggie prepares to leave, but Carl can't bear the idea of his mother reanimating, so he decides to prevent it from happening. Maggie stands at the door with the baby as Carl shoots Lori in the head, preventing her from reanimating.