In the aftermath of Godzilla's attack on Tokyo and later imprisonment at Mount Mihara in 1985,[7] the monster's cells are secretly delivered to the Saradia Institute of Technology and Science, where they are to be merged with genetically modified plants in the hope of transforming Saradia's deserts into fertile land and ending the country's economic dependence on oil wells. Dr. Genshiro Shiragami and his daughter, Erika, are enlisted to aid with the project, but a terrorist bombing destroys the institute's laboratory, ruining the cells and killing Erika.

Five years later, Shiragami has returned to Japan and merged some of Erika's cells with those of a rose in an attempt to preserve her soul. Meanwhile, scientist Kazuhito Kirishima and Lieutenant Goro Gondo of the JSDF are using the Godzilla cells they collected to create "Anti-Nuclear Energy Bacteria" (ANEB), hoping it can serve as a weapon against Godzilla should it return. They attempt to recruit Shiragami to aid them, but are rebuffed.

International tensions increase over the Godzilla cells, as they are coveted by both the Saradia Institute of Technology and Science and the American Bio-Major organization. An explosion from Mount Mihara causes tremors across the area, including Shiragami's home, badly damaging the roses. Shiragami agrees to join the JSDF's effort and is given access to the Godzilla cells, which he secretly merges with one of the roses. A night later, rival Bio-Major and Saradian agents break into Shiragami's lab, but are attacked by a large plant-like creature which later escapes to Lake Ashi and is named "Biollante" by Shiragami.

Bio-Major agents plant explosives around Mount Mihara and blackmail the Diet of Japan, warning the explosives will be detonated and thus free Godzilla if the cells are not handed over. Kirishima and Gondo attempt to trade, but Saradian agent SSS9 thwarts the attempt and escapes with the cells. The explosives are detonated, and Godzilla is released. Godzilla attempts to reach the nearest power plant to replenish its supply of nuclear energy, but Biollante calls out to Godzilla.

Godzilla arrives at the lake to engage Biollante in a vicious battle, and emerges as the victor. Godzilla then proceeds toward the power plant at Tsuruga, but psychic Miki Saegusa uses her powers to divert it toward Osaka instead. The city is quickly evacuated before Godzilla makes landfall. A team led by Gondo meet Godzilla at the central district and fire rockets infused with the ANEB into its body. Gondo is killed in the process, and Godzilla leaves unharmed.

Kirishima recovers the cells and returns them to the JSDF. Shiragami theorizes that if Godzilla's body temperature is increased, the ANEB should work against it. The JSDF erects microwave-emitting plates during an artificial thunderstorm, hitting Godzilla with lightning and heating up its body temperature during a battle near the shores of Wakasa Bay. Godzilla is only moderately affected, but Biollante, having obtained a more powerful form, arrives to engage Godzilla in battle once again.

After a long battle, the fight ends after Godzilla fires an atomic heat ray inside Biollante's mouth, severely injuring Biollante. An exhausted Godzilla collapses on the beach as the bacterial infection finally takes hold, and Biollante splits apart into glowing spores which rise into the sky, forming an image of Erika among the stars. Shiragami, watching the scene, is shot by SSS9. Kirishima chases the assassin and, after a brief scuffle, SSS9 is killed by a microwave-emitting plate activated by Sho Kuroki. Godzilla reawakens and leaves for the ocean.