Famed astrophysicist Neil deGrasse Tyson takes a tour of the Solar System and the known universe establishing the components of Earth's "address" within the Virgo Supercluster. He then shares the story of the person who championed an expansive understanding of Earth's place in the universe by presenting Renaissance Italian Giordano Bruno's vision of the universe as a limitless expanse of space and time. He then makes an exploration into the Cosmic Calendar, which dates back to the dawn of the Big Bang (similar to the presentation from episode 1 of the original series). The episode ends with deGrasse Tyson narrating how he met his mentor Carl Sagan, who hosted the first Cosmos series.

Sagan discusses the story of the Heike crab and artificial selection of crabs resembling samurai warriors, as an opening into a larger discussion of evolution through natural selection (and the pitfalls of intelligent design). Among the topics are the development of life on the Cosmic Calendar and the Cambrian explosion; the function of DNA in growth; genetic replication, repairs, and mutation; the common biochemistry of terrestrial organisms; the creation of the molecules of life in the Miller-Urey experiment; and speculation on alien life (such as life in Jupiter's clouds). In the Cosmos Update ten years later, Sagan remarks on RNA also controlling chemical reactions and reproducing itself and the different roles of comets (potentially carrying organic molecules or causing the Cretaceous–Paleogene extinction event).

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.

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.

Professor Brian Cox journeys across the vastness of time and space revealing epic moments of sheer drama that changed the universe forever.
The series begins this epic exploration of the cosmos with a hymn to the great luminous bodies that bring light and warmth to the universe: the stars. It is estimated that there are two hundred trillion stars in the universe, each playing their part in an epic story of creation- a great saga that stretches from the dawn of time, with the arrival of the first star, through diverse generations until the arrival of our own star, the sun, and a civilization that has grown up in its light.

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).