On 11 December 1927, the political leadership of the CCP ordered about 20,000 communist-leaning soldiers and armed workers to organize a "Red Guard" and take over Guangzhou. The uprising occurred despite the strong objections of communist military commanders, as the communists were badly armed - just 2,000 of the insurgents had rifles. Nevertheless, rebel forces captured most of the city within hours using the element of surprise, despite a huge numerical and technical advantage held by government troops. After this initial success for the communists, however, the 15,000 National Revolutionary Army (NRA) troops in the area moved into the city and started to push back the insurgents. After five more NRA divisions arrived in Guangzhou, the uprising was quickly crushed. The insurgents suffered heavy casualties, while the survivors had to flee the city or go into hiding. The Comintern, especially Neumann, were later blamed for insisting that the communists had to hold onto Guangzhou at all cost. Zhang Tailei, the leading Red Guard organizer, was killed in an ambush as he returned from a meeting. The takeover dissolved by the early morning of December 13, 1927.

In the resulting purges, many young communists were executed and the Guangzhou Soviet became known as the "Canton Commune", "Guangzhou Commune" or "Paris Commune of the East"; it lasted only a short time at the cost of more than 5,700 communists dead and an equal number missing. Around 8 p.m. on 13 December, the Soviet consulate in Guangzhou was surrounded and all its personnel were arrested. In the accident the consulate diplomats Ukolov, Ivanov and others were killed. Ye Ting, the military commander, was scapegoated, purged and blamed for the failure, despite the fact that the obvious disadvantages of the communist force was the main cause of the defeat, as Ye Ting and other military commanders had correctly pointed out. Despite being the third failed uprising of 1927, and reducing the morale of the communists, it encouraged further uprisings across China.

There were now three capitals in China: the internationally recognized republic capital in Beijing, the CCP and left-wing KMT at Wuhan and the right-wing KMT regime at Nanjing, which would remain the KMT capital for the next decade. This marked the beginning of a ten-year armed struggle, known in mainland China as the "Ten-Year Civil War" which ended with the Xi'an Incident when Chiang Kai-shek was forced to form the Second United Front against invading forces from the Empire of Japan.