The astronaut family of Dr. John Robinson, accompanied by a pilot and a robot, set out in the year 1997 from an overpopulated Earth in the spaceship Jupiter 2 to travel to a planet circling the star Alpha Centauri. The Jupiter 2 mission is sabotaged by Dr. Zachary Smith (an agent for an unnamed foreign government) who slips aboard the spaceship and reprograms the robot to destroy the ship and crew. However, Smith is trapped aboard, and his excess weight alters the craft's flight path and places it directly in the path of a massive meteor storm. Smith manages to save himself by prematurely reviving the crew from suspended animation. The ship survives, but the damage caused by Smith's earlier sabotage of the robot leaves the crew lost in space. The Jupiter 2 crash-lands on an alien world, later identified by Will as Priplanus, where they spend the rest of the season and survive a host of adventures. Smith remains with the crew and acts as a source of comedic cowardice and villainy, exploiting the eternally forgiving nature of Professor Robinson.

The repaired Jupiter 2 launches into space once more, to escape the destruction of Priplanus following a series of cataclysmic earthquakes. The Robinson's crash-land on a strange new world, to become planet-bound again for another season.

The Jupiter 2 travels freely in space, visiting a new world in each episode, as the family attempts to either return to Earth or else at least reach their original destination in the Alpha Centauri system. A newly built "Space Pod" provides a means of transportation between the ship and passing planets, allowing for various escapades.