Domitien began her political career in the Social Evolution Movement of Black Africa, the country's only legal political party at the time, being appointed vice president of the party in 1972. On January 2, 1975, the dictator Jean-Bedel Bokassa formed a new government and introduced the post of prime minister, appointing Domitien to the position. She was the first woman to serve as prime minister of an African nation.
Her relationship with Bokassa soured after he began discussing the possibility of instituting a monarchy with himself as emperor. When Domitien openly rejected the plans, she was promptly fired and her cabinet was dismissed (April 7, 1976). With the overthrow of the Bokassa monarchy in September, 1979, Domitien was arrested and brought to trial on charges of covering up extortion committed by Bokassa during her tenure as prime minister. She served a brief prison term, after which she was prohibitted from returning to politics, though she remains a prominent figure, both as a former politician and as a businesswoman.