An ethnic Hutu, Mpiranya was born in Gitarama prefecture. In 1993, he held the rank of major in the Rwandan Armed Forces and was second-in-command of military operations and intelligence (S2 and S3) in the Presidential Guard Battalion. Later the same year, he was appointed Commander of the Presidential Guard Battalion.
The ICTR indictment alleges that between 1990 and 1994, Mpiranya and other officers conspired to exterminate the Tutsi civilians and political opponents, and helped to train interahamwe and militia groups who committed the genocide.
On 5 January 1994, the day that the Broad-Based Transitional Government specified by the Arusha Accords was to be sworn in, Mpiranya prevented the access of political opponents onto the premises of the Conseil national de développement, particularly Lando Ndasingwa and his Liberal Party. This had the result that the only member of the Transitional Government who had been sworn in was President Habyarimana.
After Habyarimana's death and the start of the genocide, members of the Presidential Guard presumedly led by Mpiranya "tracked down, arrested, sexually assaulted, and killed" Rwandan Prime Minister Agathe Uwilingiyimana. They also took into custody 10 Belgian peacekeepers from UNAMIR who had been guarding her house, who were later gruesomely killed.They were accompanied in this by members of the Para-Commando Battalion and the A company of the Reconnaissance Battalion, led by Captain Innocent Sagahutu.
Simultaneously, other members of the presidential guard and other army units undertook similar actions against other opposition figures.
On the morning of 7 April, Mpiranya was told by members of the Presidential Guard that Faustin Rucogoza, the Minister of Information, and his wife were presently being detained at the Presidential Guard camp. He allegedly responded by asking his soldiers why they were keeping them. Shortly afterwards, both were killed in the camp.
Mpiranya fled Rwanda after the RPF victory.
In an indictment amended on 25 September 2002, the International Criminal Tribunal for Rwanda (ICTR) charged Mpiranya with "conspiracy to commit genocide, genocide, crimes against humanity, and violations of the Geneva Convention."
For several years Mpiranya was still at large and believed to be with other Rwandan émigrés in the Democratic Republic of the Congo or in Zimbabwe.
On 25 September 2002, Mpiranya was indicted by the U.N.'s International Criminal Tribunal for Rwanda (ICTR). He was charged with genocide, conspiracy to commit genocide, complicity in genocide, crimes against humanity and war crimes. Mpiranya remained at large and was one of the most wanted men by the Tribunal. The US government put a prize on his head in the Rewards for Justice Program
In February 2010, Mpiranya was reported by Belgian authorities to be sheltered by the Zimbabwean government, operating businesses in Harare, on top of acting as mercenary for the ruling party ZANU-PF to silence the opposition.
In August 2010, Rwanda appealed for United Nations intervention in its diplomatic row after the Zimbabwean government refused to extradite Protais Mpiranya to the ICTR. Mpiranya allegedly stayed in Norton, about 40 km west of the capital Harare, where he allegedly stayed since his arrival in Zimbabwe in 2001. Security sources said that the Harare authorities were not keen on giving up the fugitive to whom they feel indebted over his reconnaissance role during the 1998–2001 Democratic Republic of Congo civil war. Mpiranya was instrumental during the DRC war after he worked side by side with southern African Allied forces, which included Zimbabwe, Angola and Namibia. He is believed to have supplied strategic information about the Rwandan military and also mobilised and trained Rwandans in refugee camps in eastern DRC to fight against the Rwandan army. Rwanda's Prosecutor General Martin Ngoga said the International Criminal Tribunal of Rwanda (ICTR) should move and bring Proitas Mpiranya to book. The two nations backed opposite sides in the DRC war. The row escalated after Zimbabwe accused Rwandan secret agents of illegally entering the country in pursuit of Mpiranya. Kigali denied the allegations, saying it would follow proper procedures to seek the extradition of Mpiranya. This was the second time that Zimbabwe has refused to extradite African officials accused of genocide in their own countries. It has refused to hand over former Ethiopian dictator Mengistu Haile Mariam who is wanted in his country for mass murder.
Despite a Zimbabwean official denying he was in the country in 2011, Zimbabwe's police announced in September 2012 that they have commenced a manhunt for Mpiranya. The UN's war crimes tribunal on Rwanda offered a USD5 million for his capture.