Four and a half years have passed since High School graduation. Lucas is now coaching the Ravens with the assistance of Skills and is in a relationship with his book editor, Lindsey Strauss (guest star, Michaela Mc Manus), who urges him to write a second novel that will match the success of his first. Nathan and Haley are raising their son Jamie (Jackson Brundage) in Tree Hill, where an accident four months previously left Nathan near-paralyzed and his basketball dreams diminished. Haley is a teacher at Tree Hill High while Mouth is an unemployed sportscaster looking for work. Brooke is undoubtedly the most successful of the group, having turned Clothes Over Bros into a multi-million dollar company, which she is running from New York. Peyton is in Los Angeles working as "the assistant's assistant" at a record company. Feeling undervalued and disrespected, she quits and after talking on the phone, she and Brooke realize that they will never be as happy as they were in Tree Hill so they return home together.

In Tree Hill, Brooke opens a Clothes Over Bros store in place of Karen's Café (Karen and Lily having left Tree Hill to travel the world) and buys a new house for herself and Peyton. Her company CEO is later revealed to be her over-controlling, cold-hearted mother Victoria, (guest-star Daphne Zuniga) who comes to Tree Hill and tries to get things back under her control, undermining Brooke and her friends. Brooke begins dating TRIC bartender Owen (guest star Joe Manganiello), and takes him to New York where they stumble upon Rachel who has taken an overdose in Brooke's apartment. After Victoria forced Brooke to fire her from her job as a Clothes Over Bros model, Rachel's drug woes spiralled out of control. After Owen revives her and Brooke takes her back to Tree Hill, Rachel begins to get her life back on track, but Victoria lashes out at her and Rachel leaves for parts unknown with Brooke's money. When she learns that Victoria was responsible for Rachel's departure, Brooke fires her - both as her CEO and her mother.

Peyton starts her own record label, funded by Brooke, and finds her first artist Mia Catallano (guest star, Kate Voegele) in a group with a cocky lead singer named Jason (guest star, Kevin Federline) whom she fires over his attitude problem. Peyton soon turns Mia into a star and is then approached by Haley, who has decided to make a comeback in music. Meanwhile, Peyton also struggles with her feelings for Lucas, creating some animosity between her and Lindsey, who is revealed to have become Lucas' editor the day after he and Peyton broke up when she turned down his proposal three years earlier. After Lucas and Peyton inevitably kiss, he and Lindsey get engaged and Peyton tells Lucas that she will sacrifice her love for him to be a good friend, just as Keith did for Karen all those years ago. Peyton and Lindsey also bury the hatchet but Peyton finds it difficult to watch as Lucas and Lindsey prepare to marry.

Mouth finally finds himself a job in the archiving department at a local TV station. He begins an unexpected affair with his boss, Alice (guest star, Kelly Collins Lintz) which kick-starts his career but he begins to feel bad about it and starts dating Brooke's assistant Millicent Huxtable (guest star Lisa Goldstein), so Alice fires him. However, he manages to keep his job when at the last minute another office affair involving Alice is exposed, as she was sleeping with several other employees. He is given an on air position but loses it after refusing to air Lucas' blow-up. His relationship with Millicent goes from strength to strength when she moves in with him, Skills, Junk and Fergie. Tim and Bevin are revealed to have married and had a son, Nathan, together.

Nathan gets his life back on track, realising that he is at risk of losing Haley and Jamie if he continues drinking himself into oblivion. He becomes a mentor to Quentin Fields (guest star, Robbie Jones) a Raven and troublesome student of Haley's while Haley hires a nanny named Carrie (guest star, Torrey De Vitto) for Jamie, though Carrie is soon revealed to be psychotic - she tries to seduce Nathan and claim him and Jamie for herself. When Carrie climbs into the shower with Nathan, he does nothing to stop her, believing her to be Haley. When Haley catches them together, she throws them both out and after Jamie almost drowns while Nathan and Haley are arguing, Haley tells Nathan that she wants a divorce. After serving five years in prison for Keith's murder, Dan is released on parole.

In the show's one hundreth episode, Lucas and Lindsey's wedding day dawns. Karen and Lily return for the occasion with Andy, who has begun seeing Karen again. Haley confronts Lucas about the copy of his second novel, which he gave her to read - she believes it to be a story about his love for Peyton, though Lucas denies this. Dan shows up at the church but is turned away by Haley, who continues to give Nathan the cold shoulder as he dreams of a reconciliation. At the altar, Lucas makes his vows and Peyton is devastated as she watches on from the congregation, but as Lindsey is making her vows, she makes the same realisation as Haley - that Lucas' story is about his love for Peyton. Because of this, Lindsey leaves Lucas at the altar and Brooke later reveals to Peyton her desire to start a family. Before they can discuss this any further, Mouth and Millicent arrive with the news that Jamie has been abducted. After his earlier appearance, everyone believes Dan to have taken Jamie, though his captor is revealed to be Carrie, who is followed by Dan. He threatens to kill her if she ever comes near his family again and later returns Jamie to a relieved Nathan and Haley. Everyone is horrified when Dan shows up at the house, this being the first time many have seen him since he was convicted for Keith's murder five years previously.

Four weeks pass and after marriage counselling, Nathan and Haley reunite, hiring Deb to be Jamie's new nanny and bringing their family back together. Nathan decides he wants to make a comeback in basketball, while Peyton agrees to record an album with Haley and Deb and Skills sleep together after meeting online, unaware of who the other person was. Dan tries to become a part of Jamie's life, though Nathan, Haley and Deb forbid it, causing Dan to reveal that he is dying of HCM and wants to use the six months he has left to make amends with his family.

Brooke begins to work on having her own family, announcing that she wants to have a baby. Turned down for adoption, she is given temporary custody of Angie, a little girl from a foreign country who is in the US for special surgery, leading Owen to break up with her, using his good friend Chase, Brooke's Clean Teen ex, as the messenger. Through her struggles with being a mother and taking care of the baby, she gets closer to Lucas and is relieved that Angie's surgery is a success. Lucas convinces Lindsey to continue her work on editing his novel, hoping that this will bring them back together, though Lindsey insists to Lucas that she has moved on and is now seeing someone else. As a result, an enraged Lucas attacks a player at one of the games, getting himself suspended from coaching, before drowning his sorrows at TRIC and telling Peyton he hates her and she ruined his life.

In the season finale, Brooke is heartbroken when she must send Angie home and turns to Lucas for support. After a week of binge-drinking, Lucas decides he needs to make some important choices about his future while Peyton tries to deal with Lucas' revelation that he hates her. Lucas visits Peyton and tells her that this is not the case; its just difficult for him to see her again after all this time. Lindsey returns to give Lucas the finished copy of his novel and to say goodbye. She later leaves him a message, informing him that she is not seeing anyone and that she misses him everyday. With Millicent's support, Mouth quits his job and appears to be contemplating a transfer to Omaha. Skills and Deb continue their clandestine relationship while Nathan and Haley are pleased when Jamie overcomes his fear of going back in the pool after his near-drowning experience there. Dan contemplates killing Reverend Carter, the critically ill man who is ahead of him on the waiting list for a heart transplant, but later decides not to for Jamie's sake. Nature takes its course and the reverend passes away. Dan is overjoyed but is ironically knocked down by a car moments before his bleeper goes off to tell him he is ready for his transplant. Nathan and Haley both celebrate comebacks in their respective fields of basketball and music when he scores against Quentin and she records her new song. At the airport, Lucas makes a phone call. Brooke (waiting for a call about Angie), Peyton (waiting for a call about her mother) and Lindsey (waiting for a business call) simultaneously answer their phones and Lucas tells the girl on the receiving end that he has two tickets to Las Vegas and invites her, to come with him tonight and get married.