Nine years ago, the American Discovery One's mission to Jupiter mysteriously failed. As depicted in 2001: A Space Odyssey, Discovery's HAL 9000 computer "Hal" (Douglas Rain)malfunctioned, killing four astronauts. The fifth, David Bowman, disappeared into a large, alien Monolith orbiting the planet. Heywood Floyd (Roy Scheider), head of the National Council on Astronautics, received the blame for the failure and left NCA.
Although tension is growing between the United States and the Soviet Union, both nations prepare missions to determine what happened to Discovery. Although the Soviet Alexei Leonov will be ready before the American spaceship, the Soviets need American astronauts to help investigate Hal's malfunction and to board an American spacecraft. The US government agrees to a joint mission since Discovery's orbit is deteriorating and it will crash into Jovian moon Io before the US ship is ready. Floyd, Discovery designer Walter Curnow (John Lithgow), and HAL 9000 creator Chandra (Bob Balaban) join the Russian mission.
Upon Leonov's arrival in the Jovian system, captain Tanya Kirbuk (Helen Mirren) and the other Soviets wake Floyd early from his hibernation because they have detected chlorophyll and other chemical signatures of life on the frozen moon Europa. A burst of electromagnetic radiation destroys an unmanned probe from Leonov and all telemetry records before the probe takes close-up pictures. Floyd suspects that it is a warning to keep away from Europa.
After surviving a dangerous aerobraking through Jupiter's atmosphere Leonov finds Discovery abandoned but undamaged, orbiting the planet close to Io, rotating on an axis at the center of it's spine. Curnow travels with Cosmonaut Max Brailovsky, and the two, in a risky EVA, enter the spinning ship. Curnow reactivates the ship and Chandra restarts Hal, which Bowman had deactivated before Discovery arrived at Jupiter. Brailovsky (Elya Baskin) travels to the Monolith in an EVA pod, but a burst of energy that emerges from the Monolith and heads to Earth consumes him. Bowman, now an incorporeal being, appears on his widow's television and wishes her farewell. He visits his terminally ill mother in a nursing home and combs her hair before she dies.
Chandra discovers the reason for Hal's malfunction: The NSC ordered the computer to conceal from Discovery's crew the fact that the mission was about the Monolith. This conflicted with Hal's basic function of open, accurate processing of information, causing him to suffer a mental breakdown.
The tensions between the United States and Soviet Union escalate to what is "technically a state of war", and the US government orders Floyd, Curnow, and Chandra to move into Discovery. Both crews plan to leave Jupiter when a launch window opens in several weeks. Bowman appears to Floyd, warning him that they must leave Jupiter within two days because "something wonderful" will happen. Although Kirbuk is skeptical of Floyd's report, the Monolith suddenly disappears and a growing black spot appears on the Jovian surface. The spot is a vast grouping of Monoliths that is rapidly increasing in number, shrinking Jupiter's volume, increasing the planet's density, and modifying the chemical properties of its atmosphere.
The Monolith's disappearance convinces the two crews that they must leave soon. Since neither ship can reach Earth with an early departure, they work together to use Discovery as a booster rocket for Leonov. Tension arises when Hal is not told that the Discovery will be left stranded in space, and possibly destroyed; Chandra fears that another deception may cause Hal to again malfunction. During the launch countdown Chandra tells the computer the truth. Hal agrees that it must sacrifice itself for the human beings on board Leonov to complete Discovery's mission.
Leonov leaves Jupiter just before the Monoliths engulf Jupiter and increase its density to the point that nuclear fusion occurs, transforming the planet into a small star. Bowman commands Hal to repeatedly broadcast a final message to Earth:
ALL THESE WORLDS
ARE YOURS EXCEPT
USE THEM TOGETHER
USE THEM IN PEACE
A wave of hot plasma erupts from the forming star, incinerating Discovery.
The new star's miraculous appearance inspires the American and Soviet leaders to seek peace. Europa gradually transforms from an icy wasteland to a humid jungle covered with plant life. A Monolith stands in a swamp, waiting for intelligent life forms to evolve.