Beginning with the separation of the fuzzy thinking and pious fraud of astrology from the careful observations of astronomy, Sagan follows the development of astronomical observation. Beginning with constellations and ceremonial calendars (such as those of the Anasazi), the story moves to the debate between Earth and Sun-centered models: Ptolemy and the geocentric worldview, Copernicus' theory, the data-gathering of Tycho Brahe, and the achievements of Johannes Kepler (Kepler's laws of planetary motion and the first science-fiction novel).

Sagan discusses comets and asteroids as planetary impactors, giving recent examples of the Tunguska event and a lunar impact described by Canterbury monks in 1178. It moves to a description of the environment of Venus, from the previous fantastic theories of people such as Immanuel Velikovsky to the information gained by the Venera landers and its implications for Earth's greenhouse effect. The Cosmos Update highlights the connection to global warming.

Carl Sagan teaches students in a classroom in his childhood home in Brooklyn, New York, which leads into a history of the different mythologies about stars and the gradual revelation of their true nature. In ancient Greece, some philosophers (Aristarchus of Samos, Thales of Miletus, Anaximander, Theodorus of Samos, Empedocles, Democritus) freely pursue scientific knowledge, while others (Plato, Aristotle, and the Pythagoreans) advocate slavery and epistemic secrecy.

Ideas about time and space are explored in the changes that constellations undergo over time, the redshift and blue shift measured in interstellar objects, time dilation in Albert Einstein's theory of relativity, the designs of both Leonardo da Vinci and spacecraft that could travel near light speed, time travel and its hypothetical effects on human history, the origins of the Solar System, the history of life, and the immensity of space. In Cosmos Update, the idea of faster-than-light travel by wormholes (researched by Kip Thorne and shown in Sagan’s novel Contact) is discussed.

Questions are raised about the search for intelligent life beyond the Earth, with UFOs and other close encounters refuted in favor of communications through SETI and radio telescope such as the Arecibo Observatory. The probability of technically advanced civilizations existing elsewhere in the Milky Way is interpreted using the Drake equation and a future hypothetical Encyclopedia Galactica is discussed as a repository of information about other worlds in the galaxy. The Cosmos Update notes that there have been fewer sightings of UFOs and more stories of abductions, while mentioning the META scanning the skies for signals.

The word Anunnaki means "princely seed" or "princely blood". The idea is that the Anunnaki were direct creations of Anu, who was regarded as the father and king of the gods. Ancient Aliens: "In the ancient texts of Sumeria we have descriptions of these being descending from the sky called the Anunnaki. The term Anunnaki means 'those who from the heavens came."