The narrative of Zetsumetsu Dōbutsu Monogatari centers on animals that have been driven to extinction by human actions, examining the specific historical circumstances and human behaviors that led to their permanent disappearance from the earth. The manga argues that unlike prehistoric animals such as the mammoth, which were hunted by primitive ancestors for survival, the modern species depicted were eradicated not out of necessity, but because of human greed, vanity, selfishness, and the relentless pursuit of profit. The work serves as a record of these events, aiming to expose the uglier aspects of human nature through the tragic fates of these lost creatures.

The story is told across a series of episodic chapters, each dedicated to a different extinct animal or bird. The first volume features eight species including the dodo of Mauritius, the massive Steller's sea cow, the passenger pigeon, the great auk, the American bison (which narrowly escaped total extinction), the Pyrenean ibex, the northern white rhinoceros, and the Japanese wolf. Each chapter reconstructs the animal's interaction with humans, from initial contact and exploitation to eventual decline and the moment of final loss. A second volume continues this theme with another eight species, including the Tasmanian tiger (thylacine), the Chinese river dolphin (baiji), the giant moa, and the Pinta Island tortoise, explicitly framing the narrative as a story connected to the present day and questioning why humanity causes extinction and whether a future without it is possible. A third volume is also available, covering the mammoth, the aurochs, and the quagga.

The setting shifts with each chapter to the specific geographic location and time period of each extinction, ranging from remote islands like Mauritius to the seas of the North Pacific and the forests of Japan. The manga presents a consistently somber and mournful tone, focusing on the irreversible finality of extinction. While grounded in historical and scientific fact, with supervision from extinction specialist and author Tadashi Imaizumi, the narrative employs creative storytelling to illustrate the emotional weight of these events. The overarching narrative arc is a chronological and thematic exploration of human-caused extinction, moving from well-known cautionary tales like the dodo to more complex cases, prompting reflection on humanity's relationship with the natural world and the moral responsibility to prevent further losses.