The first three seasons of Sliders were aired by the Fox Network. Originally canceled after the first season, the series was renewed after a fan protest. After Fox canceled the show again after three seasons, the series moved to The Sci-Fi Channel for its final two seasons. The last new episode first aired on December 29, 1999 in the United Kingdom, and was broadcast on The Sci-Fi Channel on February 4, 2000.

The nature of the show changed throughout the seasons. The first two seasons focused on alternate histories and social norms, with the consensus amongst the creative team maintaining these two seasons to be largely superior to what would come later on during the series' third season. These stories explored what would have happened, for example, if America had been conquered by the Soviet Union, if Britain had won the American War of Independence, if penicillin had not been invented, or if men were subservient to women.

The third season introduced the first significant changes to the premise of Sliders. As a result of increased Fox Network oversight (and the network-enforced, unwilling relinquishment of day-to-day creative control by creator Tracy Tormé), episodes became far more action-oriented, even going so far as to devolve into riffs on major genre feature films (including Tremors, Species, Anaconda, Twister,The Island of Dr. Moreau, and they even went so far as to copy Buffy the Vampire Slayer). Another noticeable change was that the emotional connection between Quinn and Wade that developed throughout the first two seasons and beginning of the third was abruptly replaced by frequent, and at times innapropriate, "love at first sight" interactions with others for both. An example that stands out is "Exodus", an episode described by Tormé as "one of the worst pieces of television ever produced, and the low point of the entire series", where Quinn encourages a relationship with the wife of a disabled scientist who is helping the sliders.

For the original series' creators, this was the beginning of a downward creative trend, culminating with the firing of John Rhys-Davies by the network, and Tracy Tormé deciding not to contractually continue with the series he himself created, in light of the massive creative interference he was receiving from the network executives.

The fourth and fifth seasons saw the series moved to the Sci-Fi Channel, and a restoration of the series creators' original "alternate history" premise; the other major storyline (begun at the end of the second season, but de-emphasized during Season Three) involved the growing war against the Kromaggs.

Quinn Mallory of San Francisco, Calif., a graduate student of physics specializing in string theory, creates a device capable of opening vortices to alternate universes. He develops the technology to the extent that not only can he send items through the gateway he created, but also, with the use of a timer — a sort of space-time television remote control device — return them to their point of origin. He volunteers himself as the first living test subject. After his initial slide, he returns to find a double from another universe has caused him a bit of trouble, but also helped him solve the final missing piece in the equation for sliding, which includes a solution to the unified field theory.

His best friend Wade Welles and his professor/mentor Maximillian Arturo join him on his second test. However, the wormhole grows unstable and spirals out of control. Singer Rembrandt "Cryin' Man" Brown, driving by Quinn's house, is accidentally sucked through with them.

When faced with a life-or-death situation, the timer is activated ahead of time — more than four hours before it was scheduled to — is damaged and the original coordinates are lost. Thus, the Sliders cannot return home. This leaves them unable to control when the vortices open, or into which universe they leap, literally having to wait around in a different world for hours, days or even months before they can move on. The Sliders continue moving from universe to universe, hoping they'll find their way back home.

Common themes during this season include the exploration of political issues and the appearances of recurring characters' alternate selves, showing how their situations had changed in various realities.

The group actually arrives on their homeworld at the end of the second-season premiere episode "Into the Mystic," (However this episode was released as the last in season 2) but only has seconds to decide whether or not to stay. Quinn's gate that had always squeaked does not squeak, not knowing that his family's gardener just recently fixed it. Quinn also sees a newspaper headline that read "OJ Simpson Arrested For Double Murder" and not believing that this could possibly happen Quinn makes the assumption that they aren't in their Home World, so they leave. Other than this two-minute visit to their original world Earth Prime, the Sliders are still no closer to returning home. The Sliders encounter the Kromaggs for the very first time, in the episode "Invasion". Their presence is short-lived, but they become part of the main plot of the series in later seasons.