Musso became one of the main leaders of the Indonesian Communist Party (PKI) in the early 1920s. He was a supporter of Stalin and the Communist International in Moscow. By 1925 a group of PKI leaders were making plans for an insurrection in 1926, though this was opposed by some PKI leaders such as Tan Malaka. In 1926 Musso travelled to Singapore where he received instructions from Moscow to start a revolt against Dutch rule. Musso and another PKI leader Alimin later went to Moscow, met with Stalin, and received orders to cancel the revolt and to restrict the party's activities to radical nationalist agitation. Musso however was determined to go ahead. In November that year there were revolts led by the PKI in several cities including Batavia (now Jakarta), but the revolt was crushed by the Dutch. Musso and Alimin were arrested. Musso later went to Moscow, but returned to Indonesia in 1935 to enforce the "popular front" line ordered by the seventh Comintern congress. However he was forced to leave the country and return to the Soviet Union in 1936.
On August 11, 1948 Musso arrived back in Indonesia in Yogyakarta. On September 5 he gave a speech advocating that Indonesia align itself with the Soviet Union. A revolt developed in Madiun in East Java when some elements of the PKI militia refused to disarm. Army sources claimed that the PKI had announced the proclamation of the "Soviet Republic of Indonesia" on September 18 with Musso as its president and Amir Sjarifuddin as its prime minister. However the revolt was put down by the army. On September 30 Madiun was taken over by republican troops of the Silwangi division. Thousands of party cadres were killed and 36,000 were imprisoned. Amongst the executed were several leaders including Musso who was killed on October 31, allegedly while trying to escape from prison.