In the second year of Xianfeng (1852), the Taiping Heavenly Kingdom troops besieged Changsha, and the provincial capital was in danger. At the instigation of Guo Songtao and others, Zuo went out to defend the Qing Dynasty at the invitation of Hunan Governor Zhang. Zuo entered the city in the days of heavy gunfire. Zhang was overjoyed and entrusted all military affairs to Zuo. Zuo's suggestions of "regulating military provisions day and night, managing documents" and "guarding regional paintings" were adopted and immediately put into practice, which eventually led the Taiping Army to besiege Changsha for three months and withdraw from the north. Zuo Yisheng's fame began at that time.
In the 11th year of Guangxu (1885), Zuo died of illness in Fuzhou on July 27th (September 5th) at the age of 73. On his deathbed, he first thanked the imperial court for its gracious reception and said, "The strength of China was also a key to the Vietnam War. I have been to the south, but I haven't made a big attack yet. I am proud of my motherland. I hate my life, I can't close my eyes! " He further analyzed the crisis in China, put forward many strategies for prosperity, and advised the emperor to make his strength strong, so that "although I die, I will be indecisive for life". The imperial court posthumously awarded a teacher, posthumous title "Wen Xiang". He entered Shi Jing Zhao Zhong Temple and Xianliang Temple, and established special shrines in Hunan and other provinces, where he made meritorious service.