One day a meteor fell on Earth, spreading a new substance called Tiberium. This substance was unusual and powerful, yet highly dangerous since it turned anything it touched into Tiberium itself. By 2047, Tiberium has spread and infested most of the Earth's surface, causing an ecological catastrophe. Red Zones are areas rendered inhabitable due to the severe Tiberium infestation and constant Ion storms, covering 20% of the planet's surface. Yellow Zones are areas infested by Tiberium but they hold most of the world's population. These areas are filled with civil unrest and are war-torn and ravaged but cover 50% of the planet's surface. The remaining areas are Blue Zones, areas safe from Tiberium infestation and possibly the only salvation for humanity, covering 20% of the planet's surface.

The Global Defense Initiative upkeeps the Blue Zones, keeping them defended and using special technology to keep the Tiberium infestation at bay, while the Brotherhood of Nod takes advantage of the chaos and civil unrest in the Yellow Zones to recruit their forces. However, they hadn't been heard of for years, supposedly disappeared... until now. Kane returns, commanding the Brotherhood of Nod once again to launch a serious assault against the Global Defense Initiative and its Blue Zones, starting the Third Tiberium War. Later on an alien race called the Scrin shows up, considering the planet eradicated and looking to harvest the Tiberium, but instead get caught up in the war.

Following the tradition of the series, Command & Conquer 3 is designed to be a fast-paced game, where players build up their bases to produce a powerful fighting force to destroy their enemies. Being able to play for any of the three sides, they'll have a huge selection of infantry, vehicles and aircraft to fight with, as well as structures to aid with new technologies, upgrades and the all-powerful superweapons. Unlike most games of the genre, players do all their building from a tabbed sidebar, allowing them to create production queues and deploy structures quickly and easily. Maps also have various buildings spread around which can either be garrisoned to provide further protection or captured to give players that extra edge.

In campaign mode you can fight the war for either of the sides (the third side is only available after playing the other two), playing out the storyline through various missions with high-definition FMVs and popular actors giving you orders, and winning medals based on your performance. You can also play in skirmish against the AI, or in multiplayer (network/online) against human/computer players. Online play has support for rankings, clans, VoIP, and a new feature called BattleCast, enabling players to watch or download replays from battles directly from the website, or even provide commentary like an online sport.