A Grain of Wheat tells the story of indigenous Kenyans' resistance to British colonial control. The novel centers on a handful of individuals and their motivations for participating in the independence movement, or Mau Mau.

In a village called Thabai, the carpenter Gikonyo and his wife, Mumbi, are two individuals caught up in the struggle. Another villager, Kihika, is an outspoken revolutionary who constantly incites anti-British violence and sabotage. Two other men, Mugo and Karanja, take an oppositional stance: they believe that British rule is unshakeable, and they aim to maximize their own benefit.

Kihika and other ardent rebels conduct their campaigns from the safety of the forest. They capture a remote police station, but the British retaliate with an indiscriminate roundup of all local youth—which includes Gikonyo. Mugo, compelled to intervene when a British policeman hits a pregnant woman, is also arrested. As the violence escalates, the rebels assassinate a British official named Robson.

In a prison camp, Mugo's experience of repression changes his views, and his defiant stance earns his fellow prisoners' respect. However, the situation worsens when the warden, Thompson, fiercely crushes an uprising by having some twenty inmates killed.

Kihika returns to Thabai, where he confesses to the newly freed Mugo that he is the wanted assassin. Fearful for his own safety, Mugo betrays him to Thompson, now the area's district officer. This results in Kihika's execution.

Gikonyo's prison term is much longer: almost seven years. In the interval, the pragmatic but unethical Karanja seduces Mumbi; she becomes pregnant with their child, which she must confess to her husband when he is finally freed. To make matters worse, Karanja's collaboration has elevated him to a British-appointed chief. A broken man, Gikonyo never fully recovers.

Overall, however, the resistance movement is successful, and England finally agrees to independence. Some people resent the execution of Kihika, and a number of Thabai rebels determine to ferret out whoever betrayed him. They believe this traitor to be Karanja. Yielding to pressure, he resigns as chief. They make it clear to Mugo that he must play a role in publicly exposing the culprit. Instead, he confesses to the act, which leads them to have him killed. Mumbi returns to Gikonyo, and they resolve to make a new life together.