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.

Beginning with the origins of the universe in the Big Bang, Sagan describes the formation of different types of galaxies and anomalies such as galactic collisions and quasars. The episodes moves further into ideas about the structure of the Universe, such as different dimensions (in the imaginary Flatland and four-dimensional hypercubes), an infinite vs. a finite universe, and the idea of an oscillating Universe (similar to that in Hindu cosmology). The search into other ideas such as dark matter and the multiverse is shown, using tools such as the Very Large Array in New Mexico. Cosmos Update shows new information about the odd, irregular surfaces of galaxies and the Milky Way perhaps being a barred spiral galaxy

Sagan reflects on the future of humanity and the question of 'who speaks for Earth?' when meeting extraterrestrials. He discusses the very different meetings of the Tlingit people and explorer Jean-François de La Perouse with the destruction of the Aztecs by Spanish conquistadors, the looming threat of nuclear warfare, and the threats shown by destruction of the Library of Alexandria and the murder of Hypatia. The episode ends with an overview of the beginning of the universe, the evolution of life, and the accomplishments of humanity and makes a plea to mankind to cherish life and continue its journey in the cosmos. The Cosmos Update notes the preliminary reconnaissance of planets with spacecraft, the fall of the Berlin Wall and the end of apartheid in South Africa, and measures towards the reduction of nuclear weapons.