Command & Conquer is set in alternate timeline, after a meteorite crashed near the river Tiber in Italy. The meteorite brings with it an extremely toxic alien substance called Tiberium, which becomes extremely valuable because of its ability to absorb and crystallize precious metals from the surrounding soil. An ancient, cultic secret society called the Brotherhood of Nod claims to have foreseen the potentials of this new substance, investing in the development of technology to harvest and refine Tiberium crystals ahead of the scientific community. Nod soon controls nearly half of the supply and uses these assets to sustain a rapidly growing army of followers worldwide. The group is led by a self-proclaimed messianic figure known only as Kane.

Following a series of international terrorist bombings that culminate in the destruction of the fictional Grain Trade Center in Vienna - attacks which are quickly attributed to the Brotherhood of Nod - the United Nations Security Council realizes that Kane and Nod are commencing a global campaign of terrorism, and authorises the Global Defense Initiative to intervene on its behalf, setting a conflict in motion that escalates into a world war. The game begins soon after the arrival of Tiberium in 1995, although precise time-frames are not provided in-game.

Command & Conquer features two sub-plots based on the two playable factions of the game, combining into a single overarching story. Commanding the Global Defense Initiative's troops, the player becomes instrumental in eliminating Nod's European forces. Under the command of General Mark Jamison Sheppard, the player completes missions that range from securing a beach, to rescuing civilians and scientists, to defending GDI bases from Nod assaults. Combat occurs in countries of Central and Eastern Europe. A major plot element is an international scandal caused by a Nod media manipulation, which convinces the world that the GDI deliberately attacked and massacred the Polish city of Białystok. This leads to a cut in GDI funding, forcing the player to play several missions with limited forces. Finally, the player besieges the Temple of Nod in Sarajevo, Bosnia, which Kane uses as his main base of operations.

As a new recruit in the Brotherhood of Nod, the player initially performs tasks for the Brotherhood's second-in-command, a man known as Seth. After Seth attempts to deploy the player in an operation against the United States military without Kane's approval, Kane kills him and thereafter issues commands to the player directly. The player's goal is to drive GDI forces out of North Africa through the use of both conventional and unconventional warfare. In a ploy to secure victory for Nod, the player is assigned to gain control of GDI's space-based ion cannon, and to establish Nod's Temple in South Africa. The campaign ends with the entire African continent under Nod's control, and with the Brotherhood planning to achieve the same in Europe. The conclusion of the campaign allows the player to choose a historical landmark to destroy with GDI's hijacked ion cannon, in order to shatter GDI's public image. Potential targets include the White House, the British Houses of Parliament, the Eiffel Tower and the Brandenburg Gate.