When Icarus Base is attacked, it's inhabitants are forced to flee through the Stargate. The base was created on a distant planet to take advantage of a powerful energy supply located there. Their goal is to try and determine the purpose of the mysterious ninth symbol of the Stargate which they have never been able to lock in. In going through the Stargate, they are transported not to Earth but onto an very old, apparently uninhabited but huge spacecraft. With the group's commander injured, Lt. Scott and the chief scientist, Dr. Nicholas Rush lead the exploration of the craft. Several areas of the ship have been damaged but it is basically functional. They are able to learn that they are in fact billions of light years from Earth.

The survivors arrive on an uninhabited ship floating billions of light years away from Earth. Panic spreads throughout the group and Col. Young, who was severely injured during the escape, transfers command to Lt. Matthew Scott, before lapsing into unconsciousness. Teams led by Dr. Rush and Sgt. Greer try to make sense of the situation, while Lt. Tamara Johansen, a medic who was days away from leaving the program, is thrust into the role of chief medical officer.

The Destiny suffers a power crisis, putting the lives of the stranded crew in jeopardy and forcing them to consider abandoning the ship.

With the ship on a collision course, the crew must decide who will stay and who will flee on the shuttle to try and find a habitable planet.

Visiting a newly discovered jungle planet, the crew is amazed to recover a Kino by the gate. Downloading the Kino data, Eli discovers video of the team, which appears to have been shot during an earlier visit. The mystery of the video’s origin becomes a secondary concern as members of the team start falling ill.

Everyone is shocked when a member of the crew is found dead from a gunshot wound. While at first glance it appears to be suicide, the gun is nowhere to be found. The crew is confined to quarters while a search is performed and when the gun shows up in Col. Young’s quarters, he becomes the number one suspect.

A snafu with the communications stones lands Col. Young's consciousness in an unknown being, resulting in a standoff between the Destiny and an alien vessel and the abduction of Chloe.

The Destiny has jumped into hyperspace and is now traveling through an inter-galactic void. They've also been unable to locate Eli, Chloe and Scott who have been left behind. Dr. Rush has calculated that based on their current energy consumption, the Destiny has insufficient fuel to reach the next galaxy and they are doomed to die. The engines suddenly fail however and they arrange for an expert, Amanda Perry, to come on board via the communication stones and help them out. Perry and Rush have known each other for many years but as a quadriplegic, is experiencing what life has to offer. On Earth, Camile Wray's consciousness has been transferred to Perry's body and is wheelchair bound.

Lt. Tamara Johansen tries to track down what is causing the crew to hallucinate.

An enemy from the Milky Way has boarded the Destiny and has taken hostages. Is it possible that they know how to get back or have they stranded themselves as well?

As Young and Camille attempt to resolve the hostage crisis with Kiva, Destiny suffers from power fluctuations and blackouts due to its proximity to a binary pulsar.

Desperate for food and water, Rush directs the ship to a planet that has been locked out of Destiny's controls. Young and Wray clash over what to do with the Alliance prisoners.

The crew encounters a ship remarkably similar to Destiny, which may hold the key to their returning home.

Young is plagued by mysterious dreams where Destiny is destroyed by alien attackers no matter what he does.

Rush travels back in time to avert a disaster, meeting a past version of himself.

Chloe's body is taken over by another consciousness. Meanwhile, Dr. Volker is stricken with a mysterious illness.