His ancestors hailed from Juan 卷 (modern Yuanyang 原陽, Henan) but later moved to Pei 沛 (mocern Peixian 沛縣, Jiangsu), the home town of Liu Bang, whom he joined in 209 in his rebellion against the Qin dynasty 秦 (221-206 BC). He was made palace receptionist (zhongjuan 中涓) of Liu Bang and took over his own armies during the war against Xiang Yu 項羽, as well as during the early years of the dynasty, when the various rebelling kings like Han Xin 韓信, Ying Bu 英布 and Peng Yue 彭越 had to be crushed. Zhou Bo was appointed Defender-in-chief (taiwei 太尉) and Counsellor-in-chief (xiangguo 相國) and was given the title of Marquis of Jiang 絳侯.
Zhou Bo was known as a man of action, not as one of great words. In face of the coming end, Liu Bang, as Emperor Gaozu 漢高祖 (r. 202-195), recommended Zhou Bo to his wife, Empress Lü 呂后. He served the young Emperor Hui 漢惠帝 (r. 195-188) and, after his untimely death, his mother, the Empress Dowager Lü, as Defender-in-chief. After her death, the Empress Dowager's nephews tried to take over the control of the court. In this moment, Zhou Bo, together with Counsellor-in-chief Chen Ping 陳平, played a decisive role in annihilating the Lü family with the forces of Liu Zhang 劉章, Marquis of Zhuxu 朱虛侯. He received the Prince of Dai 代王, Liu Heng 劉恆, as the new emperor (Emperor Wen 漢文帝， r. 180-157).
While Cheng Ping was the Counsellor to the Left (zuo chengxiang 左丞相), Zhou Bo held the more eminent position of Counsellor to the Right (you chengxiang 右丞相) under the reign of Emperor Wen. Yet Zhou Bo was not a person fit for the office of Counsellor, and so he asked to be allowed to leave this post. He was again made Counsellor after the death of Chen Ping, but he renounced soon. In retirement, Zhou Bo suspected Emperor Wen of planning to kill him, and therefore constantly wore his armoury. This circumstance incited someone to slander him of rebellion, and Zhou Bo was arrested and put into jail. He was soon released because his son Zhou Sheng 周勝 was married with a daughter of the emperor, and because these relations ensured contact with Empress Bo 薄后, who supported his release.
He died a few years later in retirement. His posthumous title is "the martial marquis" of Jiang 絳武侯.