The second season consisted of 23 episodes and ran from September 21, 2004 to May 24, 2005.
After Lucas and Keith learn of Dan's heart attack, they return to Tree Hill and Dan decides he wants to get to know Lucas. Lucas cautiously enters into a relationship with his father. After Dan learns that Lucas has inherited his hypertrophic cardiomyopathy (HCM), the genetic defect which caused Dan's own heart attack, he convinces Lucas to move in with him and pays for his medication, keeping his condition a secret. Dan also agrees to stay away from Keith and his girlfriend Jules (guest star, Maria Menounos) as Lucas discovers that Dan hired Jules to make Keith fall in love with her and then break his heart to get back at Keith for sleeping with Deb. Jules leaves Keith at the altar and he leaves Tree Hill with a broken heart.
Nathan and Haley receive a visit from Haley's wild older sister, Taylor James (guest star, Lindsey McKeon) who is revealed to have been the first girl Nathan ever slept with, long before he met Haley. To make things worse, the marriage is tested even further with the arrival of Chris Keller (guest star, Tyler Hilton), a musician who convinces Haley to leave Nathan and Tree Hill to come on tour with him. In despair, Nathan attempts to kill himself by crashing a race-car but a dream makes him realize that he has to get on with life without Haley and so he allows papers to be drawn up to annul their marriage.
Peyton starts an all-ages club named TRIC but at the same time, finds herself tempted to take drugs and enters a dark place in her life, which Jake helps her out of when he returns. Jake and Peyton fall in love and begin a relationship, but Jake is forced to leave Peyton and Tree Hill once again when Nicki kidnaps Jenny and disappears with her. Brooke begins the season by forming a "Friends With Benefits" arrangement with her new neighbour, Felix Taggarro (guest star, Michael Copon), but after her parents lose all their money, Brooke discovers an inner strength she never knew she had. She runs for Student Council President and is elected over her bitter opponent, Erica Marsh (guest star, Katherine Bailess). She dumps Felix after discovering he vandalized Peyton's locker and Felix is sent to Military School by his parents. Brooke gets close to Lucas and moves into his old bedroom after her parents move to California. It is rumored that the WB show producers needed to get rid of Michael Copon because the character he portrayed on the show was more successful than expected and they were afraid that Copon would steal the spotlight from Chad Michael Murray if his character, Felix, was to have a permanent role on the show. Season 2 boasted the highest One Tree Hill viewer ratings in the shows history so far.
Lucas dates Felix's sister Anna (guest star, Daniella Alonso) but ends things with her after realizing that he loves Brooke. Anna's break-up with Lucas leaves her confused about her sexuality. After kissing Peyton in a misunderstanding, Anna starts coming to terms with the fact that she is bisexual. After coming out to her parents, Anna returns to her old Boarding School to be with her girlfriend.
Dan and Deb reconcile, united in their disapproval of Nathan's marriage. Lucas finds out Deb has developed an addiction to painkillers and after Nathan's car accident, she tries to overcome it by going to rehab, blaming her unhappy marriage to Dan for her addiction. Karen dates her business professor, the much younger Andy Hargrove (guest star, Kieren Hutchison), who makes an enemy out of Dan.
In the season finale, Andy is forced to return to New Zealand and look after his mother when she becomes very ill. Karen decides to go after him and is concerned that he hasn't checked into his hotel. Before Karen leaves Tree Hill, she thinks she sees Keith on the street opposite the café. Deb is discharged from rehab and learns that Dan tried to make Nathan feel guilty for her addiction. Deb tells Nathan that she wants them to make a fresh start away from Tree Hill and Lucas gives her the ledger of Dan's illegal business activities, which Andy uncovered. Dan blackmails Deb into giving the ledger back to him and disowns Lucas for betraying him. Nathan also disowns Lucas because he is angry with him for interfering in his family. Dan learns that Whitey has been telling Deb and Nathan a few home truths about him and threatens to have him fired. Lucas finally tells Brooke how he feels about her but she leaves for a summer in California without telling him how she herself feels. Peyton receives chilling instant-messages from someone named "WATCHMEWATCHU" and believes that it is the mysterious reporter, Ellie Harp (guest star, Sheryl Lee). Ellie comes to Peyton's house and shocks Peyton by telling her that she is her mother. Dan finds a white substance on the rim of a bottle left for him anonymously at the dealership and discovers he has been poisoned. Before Dan falls unconscious, a black-clad figure enters his office and sets it alight. Nathan moves back in with Deb but gets a surprise when he arrives home to find Haley on his doorstep. Lucas and Peyton find themselves alone on the beach together and realize that it's just the two of them this summer.