Cersei learns that her husband Robert is in danger of finding out that the children he sees as his heirs to the throne are not his. Robert meets his end as the result of a boar attack on a hunting trip, before Ned Stark tells him of the truth about his children. Cersei works quickly to instate her oldest son, Joffrey, on the throne, with her as his chief political advisor and Queen Regent. Joffrey quits listening to his mother.
Tywin decides that Cersei does not exercise enough control over her son, and sends Tyrion as an additional political advisor. Cersei and Tyrion do not get along, and constantly try to undermine each other's authority over the crown. As of the end of season 2, Tyrion has accumulated more sway over the Iron Throne, and has shipped Cersei's only daughter off against Cersei's will to be married to the prince of Dorne.
Cersei comes to fear that Margaery intends to usurp her as queen, and unsuccessfully tries to alienate Joffrey from her. Cersei is delighted when Tywin learns of the Tyrells' plan to wed Sansa Stark to Margaery's brother Loras and he intervenes to have Tyrion marry Sansa instead, but is furious when Tywin also orders her to marry Loras. When Jaime returns to King's Landing, he immediately seeks out Cersei, who is shocked to discover that his sword hand has been cut off.
Cersei has Tyrion arrested after Joffrey is fatally poisoned. It is implied that she knows Tyrion's guilt is highly unlikely, but just wants to see him dead, though Jaime refuses to carry out the order. Indeed, at Tyrion's trial, it is obvious that Cersei has manipulated the entire procedure so that the witnesses give either incomplete or entirely false testimonies to implicate Tyrion and Sansa further in the murder. When Tyrion demands a trial by combat, Cersei quickly chooses Ser Gregor "The Mountain" Clegane as her champion to diminish Tyrion's chances of acquittal, and has Bronn betrothed to a noblewoman so that Tyrion cannot choose him as his champion. Cersei's wish comes true when Tyrion's champion, Oberyn Martell, is killed by Clegane, but she still refuses to marry Loras, even threatening her father with revealing the truth about her relationship with Jaime and the parentage of her children. Tywin rebuffs her threats, though he himself is killed by an escaping Tyrion soon afterwards.
Cersei receives a threat from Dorne, where Myrcella is betrothed to Trystane Martell, and sends Jaime to Dorne to retrieve her. Tommen is married to Margaery, who tries to manipulate Tommen into sending Cersei to Casterly Rock. Fearful of losing her power, Cersei meets religious leader the High Sparrow, appointing him as the High Septon and giving him authority to re-establish the Faith Militant. In order to destabilise House Tyrell, Cersei arranges for the High Sparrow to arrest Loras for his homosexuality, with Margaery also arrested for perjury after lying to defend Loras. However, Cersei's plot backfires when Lancel, now a member of the Faith Militant, confesses to his affair with Cersei and his role in Robert's assassination, and also accuses Cersei of incest, prompting the High Sparrow to arrest her. Cersei is eventually allowed to return to the Red Keep after confessing to adultery with Lancel, but has her hair cut off and is forced to walk naked through the streets of King's Landing as atonement. Cersei returns distraught by the abuse directed at her by the smallfolk of King's Landing, but is consoled by Qyburn's successful reanimation of Ser Gregor Clegane.
Cersei remains in the Red Keep, confined to her chambers and stripped of her authority. Though Cersei accepts Tommen's apology for his lack of action in her arrest and walk of atonement, she remains looked down upon by other members of the court. Cersei learns from Tommen that the High Sparrow plans to have Margaery do a walk of atonement before Cersei's trial and conspires with the Small Council to have the Tyrell army march on the Sept of Baelor to secure Margaery and Loras' release. Their plan backfires when it is revealed that Margaery has joined the Faith of the Seven and has convinced Tommen to merge the Faith and the Crown. Despite being stripped of her allies, Cersei opts to remain in King's Landing, having named Ser Gregor as her champion in her trial by combat. However, Tommen announces that trial by combat has been abolished and replaced by trial by the Seven. Cersei arranges for a cache of wildfire to be detonated beneath the Sept during Loras' trial, killing the High Sparrow, Margaery, Loras, and the rest of the Small Council. As a direct result of Cersei's actions, Tommen commits suicide after witnessing the explosion, leaving Cersei utterly devastated, with Maggy the Frog's prophecy finally come to fruition. With House Baratheon officially extinct (technically speaking, House Baratheon became extinct with the death of Stannis Baratheon) and no one to oppose her in King's Landing, Cersei is crowned Queen of the Seven Kingdoms.
Despite nominally being ruler of Westeros, Cersei's grip to power is tenuous, with the Riverlands in upheaval following Arya Stark's massacre of House Frey, the Vale and the North declaring Ned Stark's bastard son Jon Snow King in the North, and Tyrion, Dorne, and the Reach all supporting Daenerys Targaryen, whose fleet has seized Dragonstone. She remains cold and distant in regards to Tommen's suicide, viewing it as a betrayal of their family; with no children left to protect, Cersei's prime motivation is power. Cersei reaches out to the King of the Iron Islands, Euron Greyjoy, to form an alliance, but rejects Euron's marriage proposal as she considers him untrustworthy. Euron later ambushes Daenerys' fleet and captures Yara Greyjoy, Ellaria and Tyene Sand and presents them as a "gift" to Cersei. She agrees to marry Euron after the war is won; however, she continues her affair with Jaime, no longer attempting to hide their relationship from their servants. Cersei imprisons Ellaria and Tyene in the dungeons, poisoning Tyene with the same poison used to kill Myrcella and keeping Ellaria alive to watch her daughter die and rot.
Tycho Nestoris of the Iron Bank arrives in King's Landing to request repayment of their debt. Cersei requests a fortnight in order to fulfill their request. She then has the Lannister and Tarly armies attack Highgarden, defeating the Tyrells. Olenna commits suicide following defeat, and gloats to Jaime that she was responsible for poisoning Joffrey. The Tyrell's wealth is transported safely to King's Landing, but the food the Lannisters steal from the Reach is destroyed when Daenerys attacks the caravan with her Dothraki horde and dragon Drogon. Jaime barely survives the battle, and encourages Cersei to consider a ceasefire.
Tyrion infiltrates the capital to meet with Jaime, and Jaime tells Cersei that Daenerys and Jon want to meet with Cersei to negotiate an armistice while mankind fights the threat of the White Walkers; Cersei is skeptical, but agrees, and tells Jaime that she is pregnant. Daenerys and Jon meet with Cersei in the Dragonpit on the outskirts of King's Landing, and present to her a wight reanimated by the White Walkers as evidence of their threat. Although terrified, Cersei initially refuses to agree a ceasefire, as Jon refuses to remain neutral in the war between the Lannisters and Targaryens. Tyrion speaks to Cersei in private, apparently persuading her to ally with the rival monarchs. However, she later reveals to Jaime that she intends for her enemies to wipe out each other before attacking the victor, and has sent Euron to Essos to transport the Golden Company to Westeros. Disgusted by Cersei's shortsightedness, Jaime finally abandons her side, going North on his own.