Gunfire was heard near the prison in Kinshasa, as Ne Muanda Nsemi and other inmates escaped, witnesses said.
Police are suspected to have shot dead several prisoners, witnesses added.
Mr Nsemi is a self-styled prophet and the leader of an outlawed group seeking to revive the ancient Kongo kingdom.
He was arrested, along with his three wives and son, in March following clashes between his supporters and police.
Mr Nsemi leads the Bundu dia Kongo movement, which is campaigning to restore a monarchy in parts of DR Congo, Congo-Brazzaville, Angola and Gabon.
He was an MP when he was arrested in Kinshasa after police accused him of inciting violence.
"Followers of the Bundu Dia Kongo attacked Makala prison at dawn and broke out around 50 prisoners including their guru, Ne Muanda Nsemi," government spokesman Lambert Mende said, AFP news agency reports.
A major operation is underway in Kinshasa to recapture the prisoners, reports the BBC's Mbelechi Msoshi from the city.
He saw Red Cross officials loading the bodies of several prisoners into vehicles and and transporting them to the morgue.
In January 2016, every prisoner except one escaped from a jail in eastern DR Congo. They included murder and rape convicts.
Rights groups say prisons in the country are over-crowded and badly guarded.