The decision follows weeks of consultations initiated by Samba Panza in the wake of inter-religious violence that killed 77 people in the capital Bangui in late September.
Under the shake-up announced early Friday, Joseph Bindoumi, head of the Central African League of Human Rights, replaces Marie-Noelle Koyara as defense minister, Reuters reported.
Chrysostome Sambia, a general in the gendarme, will serve as public security minister, while Dominique Said Paguindji, who previously held that post, becomes minister of justice.
The ministers of rural development and youth were also replaced.
Four people were lynched on Bangui's streets Thursday. Clashes between Muslims and Christians have spiked anew and some fear they could endanger the Dec. 13 election, meant to restore democratic rule after two years of bloodshed.
Pope Francis is to visit Bangui next month.