Zhou Yu and Cheng Pu marched into Nanjun and confronted Coss across the river. Before the two armies met, Zhou Yuxian sent Gan Ning to occupy Yiling. Coss separated some military forces and surrounded Gan Ning, who asked Zhou Yu for help. Zhou Yu adopted Lv Meng's strategy, left Ling Tong to defend the rear, and personally took Lv Meng to save Gan Ning, thus lifting the siege of Gan Ning. Zhou Yu led the troops to the North Shore and made an appointment to fight Coss. Zhou Yu rode a horse and was shot to the right. He was seriously injured and withdrew to the camp. Cao Renwen heard that Zhou Yu was ill in bed and personally commanded soldiers to attack Wu Bing. Zhou Yu stood up, patrolled the battalions and encouraged the soldiers to kill the enemy. Coss had to retreat. Sun Quan appointed Zhou Yu as a partial general and concurrently served as the prefect of Nanjun, and took Xiajun, Hanchang and Zhouling as cities to station troops in Jiangling.

After Battle of Red Cliffs, Zhou Yu proposed to Sun Quan to put Liu Bei under house arrest and directly manage the army subordinates of Liu Bei's camp, but Sun Quan disagreed. In AD 2 10 (the fifteenth year of Jian 'an), Sun Quan approved Zhou Yu's plan to conquer western Shu, but when Zhou Yu rushed back to Jiangling where he was stationed, he became seriously ill and eventually died in Baqiu at the age of 36. Sun Quan personally put on mourning clothes to mourn for Zhou Yu and was moved around. When Zhou Yu's coffin was transported back to Wu Jun, Sun Quan personally went to Wuhu to meet him, and all funeral expenses were borne by the state.