Mi Zhu was from Qu County (present-day Lianyungang, Jiangsu, China). Mi Zhu originally served as a strategist under the Xu Province Prefect Tao Qian, and he assisted in the resistance against the army of Cao Cao when they invaded Xuzhou in 193 AD. He came up with a plan to defeat Cao Cao's stronger army, involving the despatching of Liu Bei to form an alliance with Kong Rong, Prefect of Beihai and a powerful warlord. Mi Zhu served under Liu Bei after the death of Tao Qian shortly after Cao Cao's campaign in Xuzhou, and served as one of his main strategists. After Lu Bu was forced out of Xuzhou, Mi Zhu sponsored Liu Bei with all of his family wealth, and he refused to serve under Cao Cao, although Cao Cao offered him and his brother Mi Fang high ranks in his army. In 215 AD he was made ¨General Who Maintains Peace of Han¨, and he was among the mosty highly-esteemed of Liu Bei's commanders.
In 219 AD, during the Battle of Fan Castle, his brother Mi Fang defected to Eastern Wu due to his hatred of the Shu commander Guan Yu. Mi Zhu headed to Liu Bei and pleaded guilty for his brother's crime, ashamed that his brother had joined the enemy and assisted in the murder of Guan Yu. Liu Bei refused to charge Mi Zhu, as he was respected by him, but Mi Zhu fell sick from shame and died in 221 AD.