T'Challa, king of Wakanda, is dying from an illness which his sister, Shuri, believes can be cured by the "heart-shaped herb". Shuri attempts to synthetically recreate the herb after it was destroyed by Killmonger,^{[N 1]} but fails to do so before he succumbs.

One year later, Wakanda is under pressure from other nations to share their vibranium, with some parties attempting to steal it by force. Queen Ramonda implores Shuri to continue her research on the heart-shaped herb, hoping to create a new Black Panther that will defend Wakanda, but she refuses due to her belief that the Black Panther is a figure of the past. In the Atlantic Ocean, the CIA and U.S. Navy SEALs utilize a vibranium-detecting machine to locate a potential vibranium deposit underwater. The expedition is attacked and killed by a group of blue-skinned water-breathing superhumans led by Namor, with the CIA believing Wakanda to be responsible. Namor confronts Ramonda and Shuri, easily bypassing Wakanda's advanced security. Blaming Wakanda for the vibranium race, he gives them an ultimatum: deliver him the scientist responsible for the vibranium-detecting machine, or he will attack Wakanda.

Shuri and Okoye learn from CIA agent Everett K. Ross that the scientist in question is MIT student Riri Williams and arrive at the university to confront her. The group is pursued by the FBI and then by Namor's warriors, who defeat Okoye before taking Shuri and Williams underwater to meet Namor. Angered by Okoye's failure to protect Shuri, Ramonda strips her of her title as general of the Dora Milaje and seeks out Nakia, who has been living in Haiti since the Blip.^{[N 2]} Namor shows Shuri his vibranium-rich underwater kingdom of Talokan, which he has protected for centuries from discovery by the world. Bitter at the surface world for enslaving the Maya, Namor proposes an alliance with Wakanda against the rest of the world but threatens to destroy Wakanda first if they refuse. Nakia helps Shuri and Williams escape, and Namor retaliates with an attack against Wakanda, during which Ramonda drowns saving Williams. Namor vows to return in a week with his full army, and the citizens of Wakanda relocate to the Jabari mountains for their safety. Meanwhile, Ross is arrested by his ex-wife and CIA director, Valentina Allegra de Fontaine, for secretly exchanging classified intelligence with the Wakandans.

After Ramonda's funeral, Shuri uses a remnant of the herb that gave Namor's people their superhuman abilities to reconstruct the heart-shaped herb. She ingests it, gaining superhuman abilities and meeting Killmonger in the Ancestral Plane, who urges her to seek revenge. Shuri dons a new Black Panther suit and is accepted by the other Wakandan tribes as the Black Panther. Despite M'Baku's urges for peace, Shuri is determined to exact vengeance on Namor for Ramonda's death and orders an immediate counterattack on Talokan. Preparing for battle, with Ayo assuming the position of general of the Dora Milaje, Shuri bestows the Midnight Angel armor upon Okoye, who in turn recruits Dora member Aneka to join her. Williams creates an Iron Man-esque powered exoskeleton to aid the Wakandans.

Using a seafaring vessel, the Wakandans lure Namor and his warriors to the surface as a battle ensues. Shuri traps Namor in a fighter aircraft, intending to dry him out and weaken him. The pair crashes on a desert beach and fight. Shuri gains the upper hand, but realizes the similarities between their paths and implores Namo