City of Life and Death takes place in 1937, during the height of the Second Sino-Japanese War. The Imperial Japanese Army has just captured the then-capital of the Republic of China, Nanjing. What followed was known as the Nanking Massacre, a period of several weeks wherein massive numbers of Chinese prisoners of war and civilians were killed.

The film tells the story of several figures, both historical and fictional, including a Chinese soldier, a schoolteacher, a Japanese soldier, a foreign missionary, and John Rabe, a Nazi businessman who would ultimately save thousands of Chinese civilians.