As A Clash of Kings begins, the Seven Kingdoms of Westeros are locked in a bloody civil war. Joff Lannister, who is still a young boy, has recently become king, but Stannis Baratheon and Renly Baratheon both want the crown for themselves. Robb Stark, meanwhile, has recently taken the title of King of the North. Far to the north of this action, the men of the Night’s Watch leave the safety of the Wall to investigate the disappearance of the wilding people, enemies who live in primitive bands and villages in the vast wilderness north of the Wall. Meanwhile, across the narrow sea, Daenerys Targaryen leads her beleaguered band of Dothrakis in search of enough wealth and soldiers to return to Westeros and capture the Iron Throne. Simultaneous developments within these three plots constitute the major action of the novel.

Robb Stark, King of the North, tries to secure an alliance with the Greyjoys of the Iron Islands by sending Theon Greyjoy, a ward of the Stark family who has been like a brother to Robb, to negotiate. Theon, however, turns against the Starks, who kept him at Winterfell against his will, and the Greyjoys not only rebuff Robb’s offer but attack the west coast of the North. At Winterfell, young Bran Stark chafes as he is left in charge. In his dreams, he inhabits the body of his direwolf, Summer. Jojen and Meera Reed arrive at Winterfell, and the three bond over Jojen and Bran’s supernatural powers. Vainglorious Theon then attacks Winterfell, seizing Bran and Rickon as hostages. He pretends to kill Bran and Rickon, which disgusts everyone. Theon lacks men and enters into an alliance with a group led by Ramsay Bolton. This group turns on Theon, takes him captive, and decimates Winterfell. Bran, Hodor, and the Reeds escape Winterfell and head to the Wall, where Jojen will continue Bran’s mystical training. Osha takes Rickon south.

Stannis Baratheon, older brother of Robert, declares himself the rightful heir to the Iron Throne. With the support of Melisandre, a red priestess, he attacks his brother Renly, who has also declared himself king. Catelyn Stark arrives at Storm’s End to broker a truce between Stannis and Renly, but instead she witnesses the death of Renly at the hands of a mysterious shadow. She flees with Brienne of Tarth, a female knight who was part of Renly's guard. Storm’s End finally falls after Ser Davos takes Melisandre below the castle at night, where he watches her give birth to a shadow assassin much like the one Catelyn saw. Catelyn returns to Riverrun to tend to her dying father, Lord Hoster Tully. Hearing of the supposed deaths of Bran and Rickon, Catelyn goes to the dungeon to question Jaime Lannister, a skilled knight whom Robb Stark captured in battle in the previous novel.

Tyrion arrives at King’s Landing to act as Hand on behalf of his father, Lord Tywin Lannister. Against his father’s wishes, he has brought his prostitute lover, Shae. While Tyrion feels some loyalty to House Lannister, he mistrusts his sister, Cersei, and wants to see justice prevail. He fortifies the city, forging alliances with two powerful members of the royal council, Littlefinger and Varys, and banishing, killing, or imprisoning those who have committed crimes, even if said crimes were committed at Cersei’s behest. Stannis leads a massive attack against King's Landing and the Lannisters by land and sea in an effort to take the throne by force. He loses, thanks to Tyrion’s cunning and foresight and the surprise arrival of Tywin’s army. During this battle, Ser Mandon Moore attempts to assassinate Tyrion, who is saved by his squire, Podrick Payne.

Posing as a boy, Arya Stark travels north to the Wall with Yoren, a recruiter for the Night’s Watch. A vicious attack kills Yoren, but Arya escapes with her friends Gendry, Hot Pie, and Lommy Greenhands. In the process, she saves the lives of three criminals, including a man from Braavos named Jaqen H’ghar. Neither Arya nor Gendry knows, but Gendry is actually the bastard son of Robert Baratheon, who was king before Joff Lannister. Arya and her friends are captured and taken to Harrenhal to work as servants. Jaqen arrives at Harrenhal as part of a group called the Brave Companions. When he spots Arya, he promises to kill any three people Arya names in return for her saving his life and the lives of his friends. Arya has Jaqen kill two people, then forces Jaqen to help her free a group of Northmen who she believes will help her return to Winterfell. Impressed by her cunning, Jaqen gives her a coin and tells her she can always get help from a Braavosi fighter if she repeats a certain phrase he teaches her. Arya again escapes with Gendry and Hot Pie.

Meanwhile, a group of men from the Night’s Watch leave the Wall and travel into the mysterious woods to the north. They spend the night at Craster’s Keep, where Craster reveals that Mance Rayder is gathering all the wildings. They continue moving north, camping at the Fist of the First Men. Jeor Mormont sends Jon Snow and Qhorin Halfhand as reconnaissance scouts. The pair discover that the wildings are moving. Jon has a dream in which he becomes Ghost, his direwolf. Later, the events of the dream come true, implying that Jon, like his half-brother Bran, is a warg (skinchanger). Qhorin commands Jon to pretend to give up the Night's Watch and join the wildlings if they are captured, but to secretly keep gathering information. When the wildlings take Jon and Qhorin, they make the two fight to the death, and deliberately allows Jon to kill him to convince the wildlings that Jon truly means to abandon the Watch.

In the lands across the narrow sea, Daenerys Targaryen struggles. After the death of her Dothraki husband, a powerful warlord, her Dothraki following dwindled. She roams the Red Waste with a small, loyal band, including her handmaids, her bloodriders, and Ser Jorah Mormont. Her three dragons continue to grow. For a time, they camp at an abandoned city, but eventually they continue to Qarth. Although the Qartheen are intrigued by her dragons, they will not help Daenerys raise an army to capture her rightful throne or fund her crossing of the narrow sea. She is told to seek answers at the House of the Undying Ones, where she is beset by disturbing visions. One of her dragons burns it down, which angers the Qartheen. Daenerys is saved from an assassination attempt by two strangers, Strong Belwas and Arstan Whitebeard. Acting on behalf of Illyrio Mopatis, they have arrived to take Daenerys back to Pentos. She agrees.